PGE2 -oxa-phenylene compounds

ABSTRACT

This invention is a group of PGE 2  -type oxa-phenylene compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of my copending applicationSer. No. 302,567, filed Oct. 30, 1972, which was a continuation-in-partof my then copending application Ser. No. 121,572, filed Mar. 5, 1971both now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to compositions of matter, and to methods andintermediates for producing them. In particular, the several aspects ofthis invention relate to novel oxa-phenylene analogs of some of theknown prostaglandins, for example prostaglandin E₁ (PGE₁), prostaglandinE₂ (PGE₃), prostaglandin F₁ (PGF₁.sub.α and PGF₁ .sub.β), prostaglandinF₂ (PGF₂.sub.α and PGF₂.sub.β), prostaglandin A₁ (PGA₁), prostaglandinA₂ (PGA₂), prostaglandin B₁ (PGB₁), prostaglandin B₂ (PGB₂), thecorresponding PG₃ 's, and the dihydro PG₁ derivatives, to novel methodsfor producing those novel prostaglandin analogs, and to novel chemicalintermediates useful in those novel methods.

Each of the above-mentioned known prostaglandins is a derivative ofprostanoic acid which has the following structure and atom numbering:##SPC1##

A systematic name for prostanoic acid is7-[(2β-octyl)-cyclopent-1α-yl]heptanoic acid.

PGE₁ has the following structure: ##SPC2##

PGF₁ .sub.α has the following structure: ##SPC3##

Pgf₁ .sub.β has the following structure: ##SPC4##

Pga₁ has the following structure: ##SPC5##

Pgb₁ has the following structure: ##SPC6##

Each of the known prostaglandins PGE₂, PGF₂ .sub.α, PGF₂.sub.β, PGA₂,and PGB₂ has a structure the same as that shown for the correspondingPG₁ compound except that in each, C-5 and C-6 are linked with a ciscarbon-carbon double bond. For example, PGE₂ has the followingstructure: ##SPC7##

Each of the known PG₃ prostaglandins has a structure the same as that ofthe PG₂ compounds except that in each, C-17 and C-18 are linked with acis carbon-carbon double bond. For example, PGE₃ has the followingstructure: ##SPC8##

Each dihydro derivative of PGE₁, PGF₁.sub.α, PGF₁.sub.β, PGA₁, and PGB₁has a structure the same as that shown for the corresponding PG₁compound except that in each, C-13 and C-14 are linked with acarbon-carbon single bond. For example, dihydro-PGE₁ has the followingstructure: ##SPC9##

The prostaglandin formulas mentioned above each have several centers ofasymmetry. As drawn, formulas II to IX each represents the particularoptically active form of the prostaglandin obtained from certainmammalian tissues, for example, sheet vesicular glands, swine lung, andhuman seminal plasma, or by reduction or dehydration of a prostaglandinso obtained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1(1968), and references cited therein. The mirror image of each formularepresents a molecule of the enantiomer of that prostaglandin. Theracemic form of the prostaglandin consists of equal numbers of two typesof molecules, one represented by one of the above formulas and the otherrepresented by the mirror image of that formula. Thus, both formulas areneeded to define a racemic prostaglandin. See Nature 212, 38 (1966) fordiscussion of the stereochemistry of the prostaglandins.

In formulas I-IX, as well as in the formulas given hereinafter, brokenline attachments to the cyclopentane ring indicate substituents in alphaconfiguration, i.e., below the plane of the cyclopentane ring. Heavysolid line attachments to the cyclopentane ring indicate substituents inbeta configuration, i.e., above the plane of the cyclopentane ring.

Prostaglandins with carboxyl-terminated side chains attached to thecyclopentane ring in beta configuration are also known. These arederivatives of 8-iso-prostanoic acid which has the following formula:##SPC10##

A systematic name for 8-iso-prostanoic acid is7-[(2β-octyl)-cyclopent-1β-yl]heptanoic acid.

The side-chain hydroxy at C-15 in formulas II to IX is in alpha (S)configuration. See Nature 212, 38 (1966) for discussion of thestereochemistry of the prostaglandins.

PGE₁, PGE₂, dihydro-PGE₁, and the corresponding PGF.sub.α, PGF.sub.β,PGA, and PGB compounds, and their esters, acylates, andpharmacologically acceptable salts, are extremely potent in causingvarious biological responses. For that reason, these compounds areuseful for pharmacological purposes. See, for example, Bergstrom et al.,Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few ofthose biological responses are stimulation of smooth muscle as shown,for example, by tests of strips of guinea pig ileum, rabbit duodenum, orgerbil colon; potentiation of other smooth muscle stimulants;antilipolytic activity as shown by antagonism of epinephrine-inducedmobilization of free fatty acids or inhibition of the spontaneousrelease of glycerol from isolated rat fat pads; inhibition of gastricsecretion in the case of the PGE and PGA compounds as shown in dogs withsecretion stimulated by food or histamine infusion; activity on thecentral nervous system; controlling spasm and facilitating breathing inasthmatic conditions; decreasing blood platelet adhesiveness as shown byplatelet-to-glass adhesiveness, and inhibition of blood plateletaggregation and thrombus formation induced by various physical stimuli,e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP,serotonin, thrombin, and collagen; and in the case of the PGE and PGBcompounds, stimulation of epidermal proliferation and keratinization asshown when applied in culture to embryonic chick and rat skin segments.

Because of these biological responses; these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about 10 μg. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE, PGF.sub.α, PGF.sub.β, and PGA compounds are useful in thetreatment of asthma. For example, these compounds are useful asbronchodilators or as inhibitors of mediators, such as SRS-A, andhistamine which are released from cells activated by an antigen-antibodycomplex. Thus, these compounds control spasm and facilitate breathing inconditions such as bronchial asthma, bronchitis, bronchiectasis,pneumonia and emphysema. For these purposes, these compounds areadministered in a variety of dosage forms, e.g., orally in the form oftablets, capsules, or liquids; rectally in the form of suppositories;parenterally, subcutaneously, or intramuscularly, with intravenousadministration being preferred in emergency situations; by inhalation inthe form of aerosols or solutions for nebulizers; or by insufflation inthe form of powder. Doses in the range of about 0.01 to 5 mg. per kg. ofbody weight are used 1 to 4 times a day, the exact dose depending on theage, weight, and condition of the patient and on the frequency and routeof administration. For the above use these prostaglandins can becombined advantageously with other anti-asthmatic agents, such assympathomimetics (isoproterenol, phenylephrine, ephedrine, etc);xanthine derivatives (theophylline and aminophylline); andcorticosteroids (ACTH and predinisolone). Regarding use of thesecompounds see South African Pat. No. 681,055.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secrection, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 μg. to about 500 μg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about 20 mg. per kg. of bodyweight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful whenever it isdesired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, and to remove or prevent the formation ofthrombi in mammals, including man, rabbits, and rats. For example, thesecompounds are useful in the treatment and prevention of myocardialinfarcts, to treat and prevent post-operative thrombosis, to promotepatency of vascular grafts following surgery, and to treat conditionssuch as atherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF.sub.α, and PGF.sub.β compounds are especially useful asadditives to blood, blood products, blood substitutes, and other fluidswhich are used in artificial extracorporeal circulation and perfusion ofisolated body portions, e.g., limbs and organs, whether attached to theoriginal body, detached and being preserved or prepared for transplant,or attached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE₂, for example, is useful in place of or in combinationwith less than usual amounts of these known smooth muscle stimulators,for example, to relieve the symptoms of paralytic ileus, or to controlor prevent antonic uterine bleeding after abortion or delivery, to aidin expulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 μg. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful in place ofoxytocin to induce labor in pregnant female animals, including man,cows, sheep, and pigs, at or near term, or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispurpose, the compound is infused intravenously at a dose of 0.01 to 50μg. per kg. of body weight per minute until or near the termination ofthe second stage of labor, i.e., expulsion of the fetus. These compoundsare especially useful when the female is one or more weeks post-matureand natural labor has not started, or 12 or 60 hours after the membraneshave ruptured and natural labor has not yet started. An alternativeroute of administration is oral.

The PGE, PGF.sub.α, and PGF.sub.β compounds are useful for controllingthe reproductive cycle in ovulating female mammals, including humans andanimals such as monkeys, rats, rabbits, dogs, cattle, and the like. Bythe term ovulating female mammals is meant animals which are matureenough to ovulate but not so old that regular ovulation has ceased. Forthat purpose PGF₂.sub.α, for example, is administered systemically at adose level in the range 0.01 mg. to about 20 mg. per kg. of body weightof the female mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Intravaginal and intrauterineare alternative routes of administration. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal dysfunction, especially those involving blockageof the renal vascular bed. Illustratively, the PGA compounds are usefulto alleviate and correct cases of edema resulting, for example, frommassive surface burns, and in the management of shock. For thesepurposes, the PGA compounds are preferably first administered byintravenous injection at a dose in the range of 10 to 1000 μg. per kg.of body weight or by intravenous infusion at a dose in the range 0.1 to20 μg. per kg. of body weight per minute until the desired effect isobtained. Subsequent doses are given by intravenous, intramuscular, orsubcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. ofbody weight per day.

The PGE and PGB compounds promote and accelerate the growth of epidermalcells and keratin in animals, including humans, useful domestic animals,pets, zoological specimens, and laboratory animals. For that reason,these compounds are useful to promote and accelerate healing of skinwhich has been damaged, for example, by burns, wounds, and abrasions,and after surgery. These compounds are also useful to promote andaccelerate adherence and growth of skin autografts, especially small,deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the cite where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 1to 500 μg./ml. of the PGB compound or several times that concentrationof the PGE compound. Especially for topical use, these prostaglandinsare useful in combination with antibiotics, for example, gentamycin,neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example, hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

The PGE and PGF compounds are useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by PGE and PGF compounds isuseful in assisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause performation of the uterus, cervical tears, or infections. It isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the PGE and PGF compounds areadministered locally or systemically. PGE₂, for example, is administeredorally or vaginally at doses of about 5 to 50 mg. per treatment of anadult female human, with from one to five treatments per 24 hour period.PGE₂ is also administered intramuscularly or subcutaneously at doses ofabout one to 25 mg. per treatment. The exact dosages for these purposesdepend on the age, weight, and condition of the patient or animal.

The PGE, PGF.sub.α, PGF.sub.β, PGA, and PGB compounds are useful inreducing the undesirable gastrointestinal effects resulting fromsystemic administration of anti-inflammatory prostaglandin synthetaseinhibitors, and are used for that purpose by concomitant administrationof the prostaglandin and the anti-inflammatory prostaglandin synthetaseinhibitor. See Partridge et al., U.S. Pat. No. 3,781,429, for adisclosure that the ulcerogenic effect induced by certain non-steroidalanti-inflammatory agents in rats is inhibited by concomitant oraladministration of certain prostaglandins of the E and A series,including PGE₁, PGE₂, PGE₃, 13,14-dihydro-PGE₁, and the corresponding11-deoxy-PGE and PGA compounds.

The anti-inflammatory synthetase inhibitor, for example, indomethacin,aspirin, or phenylbutazone is administered in any of the ways known inthe art to alleviate an inflammatory condition, for example, in anydosage regimen and by any of the known routes of systemicadministration. The prostaglandin is administered along with theanti-inflammatory prostaglandin synthetase inhibitor either by the sameroute of administration or by a different route. For example, if theanti-inflammatory substance is being administered orally, theprostaglandin is also administered orally or, alternatively, isadministered rectally in the form of a suppository or, in the case ofwomen, vaginally in the form of a suppository or a vaginal device forslow release, for example as described in U.S. Pat. No. 3,545,439.Alternatively, if the anti-inflammatory substance is being administeredrectally, the prostaglandin is also administered rectally or,alternatively, orally or, in the case of women vaginally. It isespecially convenient when the administration route is to be the samefor both anti-inflammatory substance and prostaglandin, to combine bothinto a single dosage form.

The dosage regimen for the prostaglandin in accord with this treatmentwill depend upon a variety of factors, including the type, age, weight,sex and medical condition of the mammal, the nature and dosage regimenof the anti-inflammatory synthetase inhibitor being administered to themammal, the sensitivity of the particular individual mammal to theparticular synthetase inhibitor with regard to gastrointestinal effects,and the particular prostaglandin to be administered.

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel oxa-phenyleneprostaglandin analogs, and process for making them.

The novel prostaglandin analogs of this invention each have an oxaoxygen (--O--) and a divalent phenylene moiety ##SPC11##

in the carboxyl-terminated side chain of the prostanoic acid structure(I) or the 8-iso-prostanoic acid structure (X). These divalent groupsare located between the carboxyl group and the cyclopentane ring, andare either in addition to the six methylene portions of said chain or inplace of one to five of said methylene portions. Bonding to thephenylene ring is either ortho, meta, or para. The oxa group is betweenthe phenylene moiety and the carboxyl group.

Some of the novel prostaglandin analogs of this invention also have, inaddition, a benzene ring as part of the C-13 to C-20 chain of theprostanoic acid structure (I) or 8-iso-prostanoic acid structure (X).That benzene ring is present as a substituted or unsubstituted phenylmoiety attached as a substituent to one of the methylenes between C-15and the terminal methyl of the prostanoic acid or 8-isoprostanoic acidstructure. Alternatively, the substituted or unsubstituted phenyl moietyis attached to the terminal or omega carbon of the C-16 to C-20 portionof the chain, replacing one of the hydrogens of the terminal methyl, theentire terminal methyl, or the terminal methyl plus one to four of themethylenes adjacent to that terminal methyl.

For example, five of the novel prostaglandin analogs of this inventionare represented by the formulas: ##SPC12##

Based on its relationship to PGE₁ and prostanoic acid, the compound offormula XI is named 3-oxa-4,5-inter-p-phenylene-PGE₁. Similarly, thecompound of formula XII is named15(R)-3-oxa-3,6-inter-m-phenylene-4,5-dinor-13,14-dihydro-PGF₁.sub..alpha.,the compound of formula XIII is named8-iso-3-oxa-19-phenyl-4,7-inter-m-phenylene-5,6-dinor-PGA₁, the compoundof the formula XIV is named3-oxa-16-(4-chloro-phenyl)-3,5-inter-o-phenylene-4,17,18,19,20-pentanor-PGF₂.sub.β, and the compound of formula XV is named5,6-dehydro-4-oxa-4,5-inter-m-phenylene-PGB₂.

These names for the compounds of formulas XI to XV are typical of thenames used hereinafter for the novel compounds of this invention. Thesenames can better be understood by reference to the structure andnumbering system of prostanoic acid (Formula I, above). That formula hasseven carbon atoms in the carboxy-terminated chain and eight carbonatoms in the hydroxy-containing chain. In these names, "3-oxa" and"4-oxa" indicate an oxa oxygen (--O--) in place of the 3-methylene and4-methylene, respectively of the PG compound.

The use of "nor," "dinor," "trinor," "tetranor," "pentanor," "hexanor,"and the like in the names for the novel compounds of this inventionindicates the absence of one or more of the chain carbon atoms and theattached hydrogen atoms. The number or numbers in front of nor, dinor,etc., indicate which of the original prostanoic acid carbon atoms aremissing in the named compound.

Each of the names of the novel compounds of this invention contains(inter-p-phenylene), (inter-m-phenylene), or (inter-o-phenylene),preceded by two numbers. That indicates that p-phenylene, m-phenylene,or o-phenylene has been inserted between (inter) the two carbon atoms sonumbered in the formula of prostanoic acid.

Thus, formula XIII differs from prostanoic acid in that an oxa oxygenreplaces carbon 3, carbons 5 and 6 of prostanoic acid are missing,m-phenylene has been inserted between carbons 4 and 7 of prostanoicacid, and a phenyl has been attached to carbon 19 of prostanoic acid.Formula XIII also, of course, is an A type prostaglandin, having acarbonyl oxygen and a 10:11 double bond.

Novel compounds of this invention with the carboxyl-terminated chainattached to the cyclopentane ring in beta configuration are 8-isocompounds (formula X), and are so designated by using "8-iso" in thename. An example is the name given above for the compound of formulaXIII. If 8-iso does not appear in the name, attachment of thecarboxy-terminated chain in alpha configuration is to be assumed.

Novel compounds of this invention with epi configuration for the hydroxyat C-15 are so designated by using "15(R)" in the name. See, forexample, the name given above for the formula-XII compound. Alternately,"15-beta" is used. See. R. S. Cahn, Journal of Chemical Education Vol.41, page 116 (1964) for a discussion of S and R configurations. If"15(R)" or "15-beta" does not appear in the name, the naturalconfiguration for the C-15 hydroxy, identified as the "S" configurationfor PGE₁, is to be assumed.

Some of the novel compounds of this invention differ structurally inother ways from the known prostanoic acid derivatives, having forexample, more or fewer carbon atoms in either chain, and having one ormore alkyl and/or fluoro substituents in the chains.

The following formulas represent the novel oxaphenylene compounds ofthis invention. ##SPC13##

Formulas XVI-XIX, and XXXII represent oxa-phenylene compounds of the PGEtype. Formulas XX-XXIII, and XXXIII represent oxa-phenylene compounds ofthe PGF type. Formulas XXIV-XXVIII, and XXXIV represent oxa-phenylenecompounds of the PGA type. Formulas XXVIII-XXXI, and XXXV representoxa-phenylene compounds of the PGB type.

In formulas XVI to XXXV, the wavy line ˜ indicates attachment of thehydroxyl or the side chain to the cyclopentane ring in alpha or betaconfiguration;

G is (1) alkyl of 2 to 10 carbon atoms, inclusive, substituted withzero, one, 2, or 3 fluoro or (2) a monovalent moiety of the formula##SPC14##

wherein C_(t) H_(2t) represents a valence bond or alkylene of 1 to 10carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, withone to 7 carbon atoms, inclusive, between ##EQU1## and the ring, whereinT is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₆, wherein R₆ is hydrogen or alkyl of one to 4carbon atoms, inclusive, and wherein s is zero, one, 2, or 3, with theproviso that not more than two T's are other than alkyl; R₁ is hydrogen,alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbonatoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl,phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbonatoms, inclusive, or ethyl substituted in the β-position with 3 chloro,2 or 3 bromo, or 1, 2, or 3 iodo; Q is ##EQU2## wherein R₂ is hydrogenor alkyl of one to 4 carbon atoms, inclusive; R₃ and R₄ are hydrogen ormethyl; and R₅ is alkyl of one to 4 carbon atoms, inclusive, substitutedwith zero, one, 2, or 3 fluoro.

Likewise, in formulas XVI to XXXV, C_(g) H_(2g) represents a valencebond or alkylene of one to 4 carbon atoms, inclusive, with one or 2chain carbon atoms between --CH₂ -- and the ring; C_(j) H_(2j)represents a valence bond or alkylene of one or 2 carbon atoms with onechain carbon atom between the chain unsaturation and the ring; C_(n)H_(2n) is alkylene of one to 4 carbon atoms, inclusive; C_(p) H_(2p)represents a valence bond or alkylene of one to 4 carbon atoms,inclusive, with one or 2 chain carbon atoms between the ring and --O--,wherein C_(g) H_(2g) and C_(p) H_(2p) together represent zero to 8carbon atoms, inclusive, with total chain lengths zero to 3 carbonatoms, inclusive, and wherein C_(j) H_(2j) and C_(p) H_(2p) togetherrepresent zero to 6 carbon atoms, inclusive, with total chain lengthszero to 3 carbon atoms, inclusive.

Regarding the meaning of C_(g) H_(2g), C_(j) H_(2j), and C_(p) H_(2p) asdefined above, the novel compounds of this invention include compoundswherein a carbon atom of the phenylene moiety is attached directly tothe C-7 methylene or the C-5 =CR₄ -- in ortho, meta, or para orientationrelative to the oxa-containing portion of the carboxyl chain. When C_(g)H_(2g) represents alkylene, the chain of carbon atoms which connects theC-7 methylene to a carbon atom of phenylene will be one or 2 carbonatoms long. When C_(j) H_(2j) represents alkylene, the chain of carbonatoms which connects =CR₄ -- to a carbon atom of phenylene will be onecarbon atom long. C_(p) H_(2p) represents a valence bond or alkylene ofone to 6 carbon atoms, inclusive, with one or 2 carbon atoms between thering and the --O--. Any or all of these alkylene chains areunsubstituted or substituted with alkyl carbons in the form of one ormore alkyl groups within the total carbon content of each chain asspecified above, i.e., a maximum of 4 carbon atoms of C_(g) H_(2g), 2carbons for C_(j) H_(2j), and 4 carbons for C_(p) H_(2p). When C_(g)H_(2g) or C_(j) H_(2j) is alkylene, it is the same as or different thanC_(p) H_(2p), 8 carbon atoms being the maximum total carbon content and3 carbon atoms being the maximum total chain length for the combinationof C_(g) H_(2g) and C_(p) H_(2p), and 6 carbon atoms being the maximumtotal carbon content and 3 carbon atoms being the maximum total chainlength for the combination of C_(j) H_(2j) and C_(p) H_(2p). Toillustrate these definitions, when C_(g) H_(2g) is ethylene, C_(p)H_(2p) is methylene, or one of them is a valence bond and the other isethylene, but both are not ethylene. In this first illustration, wherethe total chain length of C_(g) H_(2g) and C.sub. p H_(2p) is 3 carbonatoms, up to 5 carbon atoms are in the alkyl substituents.

Formulas XVI through XXXV include the separate isomers wherein Q iseither ##EQU3## i.e. where the hydroxyl is in either alpha (natural) orbeta configuration. Referring to the prostanoic acid atom numbering(formula I above), the point of attachment corresponds to C-15, and,herein, regardless of the variation in the C-1 to C-7 carboxy chain,these epimers are referred to as "C-15 epimers".

Formulas XX-XXIII, and XXXIII wherein the C-9 hydroxyl (followingprostanoic acid atom numbering) is attached to the cyclopentane with awavy line ˜ include both PGF.sub.α- and PGF.sub.β-type compounds.

Included in Formulas XVII, XXI, XXV, and XXIX, are both the cis and thetrans compounds with respect to the C-5 to C-6 double bonds in thecarboxyl-terminated side chain. In all of the compounds containing theC₁₃ to C₁₄ double bond, that double bond is in trans configuration, andthe chain containing that moiety is attached to the cyclopentane ring inbeta configuration in compounds encompassed by formulas XVI to XXXV.

The novel oxa-phenylene compounds of this invention include racemiccompounds and both optically active enantiomeric forms thereof. Asdiscussed hereinabove, two structural formulas are required to defineaccurately these racemic compounds. The formulas as drawn herein areintended to represent compounds with the same configuration as thenaturally-occurring prostaglandins. However, for convenience in thecharts herein only a single structural formula is used, for example inChart D, to define not only the optically active form but also theracemic compounds which generally undergo the same reactions.

Formula XVI represents 3-oxa-4,5-inter-p-phenylene-PGE₁ (formula XIhereinabove) when C_(g) H_(2g) is ethylene, C_(p) H_(2p) is methylene, Gis n-pentyl, Q is ##EQU4## R₁ is hydrogen, C_(g) H_(2g) and C_(p) H_(2p)are attached to the phenylene in para orientation, and thecarboxyl-terminated side chain is attached to the cyclopentane ring inalpha configuration.

With regard to formulas XVI to XXXV, examples of alkyl of one to 4carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomericforms thereof. Examples of alkyl of 1 to 8 carbon atoms, inclusive, arethose given above, and pentyl, hexyl, heptyl, octyl, and isomeric formsthereof. Examples of alkyl of one to 12 carbon atoms, inclusive, arethose given above, and nonyl, decyl, undecyl, dodecyl, and isomericforms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms,inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkylof 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl,1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl,2-(1-naphthylethyl), and 1-(2-naphthylmethyl). Examples of phenylsubstituted by one to 3 chloro or alkyl of one to 4 carbon atoms,inclusive, are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl,4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of alkyl of two to 10 carbon atoms, inclusive, substituted withone to 3 fluoro, are 2-fluoroethyl, 2-fluorobutyl, 3-fluorobutyl,4-fluorobutyl, 5-fluoropentyl, 4-fluoro-4-methylpentyl,3-fluoroisoheptyl, 8-fluorooctyl, 3,4-difluorobutyl, 4,4-difluoropentyl,5,5-difluoropentyl, 5,5,5-trifluoropentyl, and 10,10,10-trifluorodecyl.

Examples of alkylene within the various scopes of C_(g) H_(2g), C_(j)H_(2j), C_(p) H_(2p), C_(n) H_(2n), and C_(t) H_(2t), as those aredefined above, are methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, and heptamethylene, and those alkylenewith one or more alkyl substituents on one or more carbon atoms,thereof, e.g., --CH(CH₃)--, --C(CH₃)₂ --, --CH(CH₂ CH₃)--, --CH₂--CH(CH₃)--, --CH(CH₃)--CH(CH₃)--, --CH₂ --C(CH₃)₂ --, --CH₂--CH(CH₃)--CH₂ --, --CH₂ --CH₂ --CH(CH₂ CH₂ CH₃)--,--CH(CH₃)--CH(CH₃)--CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ --C(CH₃)₂ --CH₂ --,--CH₂ --CH₂ --CH₂ --CH₂ --CH(CH₃)--, --CH₂ --CH₂ --CH₂ --CH₂ --CH₂--C(CH₃)₂ --, --CH(CH₃)--CH₂ --CH(CH₃)--CH₂ --CH₂ --CH(CH₃)--, and --CH₂--CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --C(CH₃)₂ --.

Examples of alkylene substituted with one or 2 fluoro and within thescope of C_(t) H_(2t), as defined above, are --CHF--CH₂ --, CHF--CHF--,--CH₂ --CH₂ --CF₂ --, --CH₂ --CHF--CH₂ --, --CH₂ --CH₂ --CF(CH₃)--,--CH₂ --CH₂ --CH₂ --CF₂ --, and --CHF--CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --CH₂--.

Examples of ##SPC15##

as defined above are phenyl, p-tolyl, m-tolyl, o-tolyl, p-fluorophenyl,m-fluorophenyl, o-fluorophenyl, p-chlorophenyl, m-chlorophenyl,o-chlorophenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl,p-trifluoromethylphenyl, p-hydroxyphenyl, m-hydroxyphenyl,o-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl,p-tetrahydropyranyloxyphenyl, m-tetrahydropyranyloxyphenyl,o-tetrahydropyranyloxyphenyl, o-ethylphenyl, m-isopropylphenyl,p-tert-butylphenyl, p-butoxyphenyl, 3,4-dimethylphenyl,2,4-diethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl,2,4-dichlorophenyl, 3,4-difluorophenyl, 2-chloro-4-methylphenyl,2-fluoro-4-methoxyphenyl, 3,5-dimethyl-4-fluorophenyl,2,6-dimethyl-4-hydroxyphenyl, and 2,4-di(trifluoromethyl)phenyl.

The novel formula XVI-XIX, and XXXII PGE-type oxa-phenylene compounds,the novel formula XX-XXIII, and XXXIII PGF.sub.α-type and PGF.sub.β-typeoxa-phenylene compounds, the novel formula XXIV-XXVII, and XXXIVPGA-type oxa-phenylene compounds, and the novel formula XXVIII-XXXI, andXXXV PGB-type oxa-phenylene compounds each cause the biologicalresponses described above for the PGE, PGF.sub.α, PGF.sub.β, PGA, andPGB compounds, respectively, and each of these novel compounds isaccordingly useful for the above-described corresponding purposes, andis used for those purposes in the same manner as described above.

The known PGE, PGF.sub.α, PGF.sub.β, PGA, and PGB compounds uniformlycause multiple biological responses even at low doses. For example, PGE₁and PGE₂ both cause vasodepression and smooth muscle stimulation at thesame time they exert antilipolytic activity. Moreover, for manyapplications, these known prostaglandins have an inconveniently shortduration of biological activity. In striking contrast, the novelprostaglandin analogs of formulas XVI to XXXV are substantially morespecific with regard to potency in causing prostaglandin-like biologicalresponses, and have a substantially longer duration of biologicalactivity. Therefore, each of these novel prostaglandin analogs is usefulin place of one of the corresponding above-mentioned knownprostaglandins for at least one of the pharmacological purposesindicated above for the latter, and is surprisingly and unexpectedlymore useful for that purpose because it has a different and narrowerspectrum of biological activity than the known prostaglandin, andtherefore is more specific in its activity and causes smaller and fewerundesired side effects than the known prostaglandin. Moreover, becauseof its prolonged activity, fewer and smaller doses of the novelprostaglandin analog can frequently be used to attain the desiredresult.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope offormulas XVI to XXXV are preferred. For example, in compounds offormulas XVI, XIX, XX, XXIII, XXIV, XXVII, XXVIII, and XXXI, it ispreferred that the carboxyl-terminated side chain contain a total of 2to 4 chain carbon atoms, inclusive, excluding the phenylene and --COOR₁,and including the C-7 methylene. In other words, preferred compounds ofthese formulas are those wherein C_(g) H_(2g) and C_(p) H_(2p) togetherrepresent zero, one, or 2 chain carbon atoms. Especially preferredcompounds of these formulas are those wherein C_(g) H_(2g) and C_(p)H_(2p) each represent a valence bond, and those wherein C_(g) H_(2g)represents a valence bond and C_(p) H_(2p) represents a single chaincarbon atom, especially methylene.

In compounds of formulas XVII, XVIII, XXI, XXII, XXV, XXVI, XXIX, XXX,XXXII, XXXIII, XXXIV, and XXXV, it is preferred that thecarboxyl-terminated side chain contain a total of 4 or 5 chain carbonatoms, excluding the phenylene and --COOR₁, and including --CH₂ --CR₃=CR₄ -- and --CH₂ --C.tbd.C--. In other words, preferred compounds ofthese formulas are those wherein C_(j) H_(2j) and C_(p) H_(2p) togetherrepresent zero or one chain carbon atoms. Included in these coumpoundsare those wherein C_(j) H_(2j) and C_(p) H_(2p) each represent a valencebond, and those wherein C_(j) H_(2j) represents a valence bond, andC_(p) H_(2p) represents a single chain carbon atom, especiallymethylene.

As used herein, a chain carbon atom is part of the direct chain carbonatoms linking the C-7 methylene or =CR₄ -- to the phenylene, thephenylene to the oxa, and the oxa to --COOR₁. Thus, the chain--CH(CH₃)--C(CH₃)₂ -- contains 5 carbon atoms but only 2 chain atoms.

Another preference for the carboxy-terminated side chain in compounds offormulas XVI to XXXV is that the phenylene be a meta-phenylene.

Another preference for the compounds of formulas XVI to XXXV is that R₂,R₃, and R₄ are hydrogen or methyl. All of those R groups can behydrogen, all can be methyl, or there can be any of the possiblecombinations of hydrogen and methyl.

Certain variations in the nature of G in the compounds of formulas XVIto XXXV are especially important. In the known PG₁ and PG₂prostaglandins, e.g., PGE₁, the portion of the molecule corresponding toG in formulas XVI to XXXI is n-pentyl. When G is unsubstituted alkyl orfluoro-substituted alkyl as defined above, there is a preference whichresults in compounds with optimum combinations of biological properties:namely that G is straight chain alkyl of 3 to 7 carbon atoms, inclusive,with or without a fluoro substituent at the 1-position , e.g.,--CHF--(CH₂)_(a) --CH₃, wherein a is one, 2, 3, 4, or 5. Especiallypreferred among these are n-pentyl and 1-fluoropentyl.

When G is substituted alkyl, it is preferred that the 1-position bemono- or di-substituted with one or two alkyl groups containing from oneto 4 carbon atoms, inclusive. Especially preferred are formulaXVI-to-XXXV compounds wherein G is substituted at the 1-position withmethyl and/or ethyl, e.g. --CH(CH₃)--(CH₂)_(c) --CH₃, --CH(C₂H₅)--(CH₂)_(c) --CH₃, --C(CH₃)₂ --(CH₂)_(c) --CH₃, --C(C₂ H₅)₂--(CH₂)_(c) --CH₃, or --C(CH₃)(C₂ H₅)--(CH₂)_(c) --CH₃, wherein c is 2,3, or 4.

When G represents ##SPC16##

as defined above, it is preferred for compounds with optimum combinationof biological properties that C_(t) H_(2t) be a valence bond, i.e., t iszero, or alkylene of one to 4 carbon atoms, inclusive, i.e., --(CH₂)_(d)-- wherein d is one, 2, 3, or 4, with or without a fluoro or alkylsubstituent on the carbon adjacent to the hydroxy-substituted carbon(C-15 in PGE₁), e.g., --CHF--(CH₂)_(e) --, --CH(CH₃)--(CH₂)_(e) --, or--C(CH₃)₂ --(CH₂)_(e) --, wherein e is zero, one, 2, or 3. Further, itis preferred that the phenyl ring when present and substituted, besubstituted at least at the para position.

In compounds of formulas XXXII to XXXV, it is preferred that C_(n)H_(2n) be methylene and that R₅ be ethyl.

Another way of expressing the above preferences for G is that when G isalkyl or fluoro-substituted alkyl it be a group represented by ##EQU5##wherein a is 2, 3, 4, or 5, and wherein R₂₁ and R₂₂ are hydrogen, alkylof one to 4 carbon atoms, inclusive, or fluoro, being the same ordifferent, with the proviso that R₂₂ is fluoro only when R₂₁ is hydrogenor fluoro.

Furthermore, when G is ##SPC17##

it is preferred that when C_(t) H_(2t) is alkylene or fluoro-substitutedalkylene it be a group represented by ##EQU6## wherein e is zero, one,2, or 3, and wherein R₂₁ and R₂₂ are as defined above.

Still another preference is that Q be ##EQU7## wherein R₂ is as definedhereinabove.

Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally, sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins. These qualities are advantageous because they facilitatemaintaining uniform levels of these compounds in the body with fewer,shorter, or smaller doses, and make possible self-administration by thepatient.

The PGE, PGF.sub.α, PGF.sub.β, PGA, and PGB type oxa-phenylene compoundsencompassed by formulas XVI to XXXV including the special classes ofcompounds described above, are used for the purposes described above inthe free acid form, in ester form, or in pharmacologically acceptablesalt form. When the ester form is used, the ester is any of those withinthe above definition of R₁. However it is preferred that the ester bealkyl of one to 12 carbon atoms, inclusive. Of those alkyl, methyl andethyl are especially preferred for optimum absorption of the compound bythe body or experimental animal system; and straight-chain octyl,nonyl,, decyl, undecyl, and dodecyl are especially preferred forprolonged activity in the body or experimental animal.

Pharmacologically acceptable salts of these formula XVI-to-XXXVcompounds useful for the purposes described above are those withpharmacologically acceptable metal cations, ammonium, amine cations, orquaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, zinc, and iron, are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine,2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,n-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris-(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The PGE, PGF.sub.α, PGF.sub.β, PGA, and PGB type oxa-phenylene compoundsencompassed by formulas XVI to XXXV including the special classes ofcompounds described above, are also used for the purposes describedabove in free hydroxy form or in the form wherein the hydroxy moietiesare transformed to lower alkanoate moieties, e.g., --OH to --OCOCH₃.Examples of lower alkanoate moieties are acetoxy, propionyloxy,butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, andbranched chain alkanoyloxy isomers of those moieties. Especiallypreferred among these alkanoates for the above described purposes arethe acetoxy compounds. These free hydroxy and alkanoyloxy compounds areused as free acids, as esters, and in salt form all as described above.

As discussed above, the compounds of formulas XVI to XXXV areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action. For intravenous injection or infusion, sterileaqueous isotonic solutions are preferred. For that purpose, it ispreferred because of increased water solubility that R₁ in the formulaXVI-to-XXXV compound be hydrogen or a pharmacologically acceptablecation. For subcutaneous or intramuscular injection, sterile solutionsor suspensions of the acid, salt, or ester form in aqueous ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers are used for oral sublingual administration. Forrectal or vaginal administration, suppositories prepared as known in theart are used. For tissue implants, a sterile tablet or silicone rubbercapsule or other object containing or impregnated with the substance isused.

The PGE, PGF.sub.α, PGF.sub.β, PGA and PGB type oxa-phenylene compoundsencompassed by formulas XVI to XXXV are produced by the reactions andprocedures described and exemplified hereinafter.

The various PGF.sub.α-type and PGF.sub.β-type oxa-phenylene compoundsencompassed by formulas XX-XXIII and XXXIII are prepared by carbonylreduction of the corresponding PGE type compounds encompassed byformulas XVI-XIX and XXXII. For example, carbonyl reduction of3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ gives a mixture of3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α and3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.β.

These ring carbonyl reductions are carried out by methods known in theart for ring carbonyl reductions of known prostanoic acid derivatives.See, for example, Bergstrom et al., Arkiv Kemi 19, 563 (1963), ActaChem. Scand. 16, 969 (1962), and British Patent Specification No.1,097,533. Any reducing agent is used which does not react withcarbon-carbon double bonds or ester groups. Preferred reagents arelithium(tri-tert-butoxy)aluminum hydride, the metal borohydrides,especially sodium, potassium and zinc borohydrides, and metal trialkoxyborohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alphaand beta hydroxy reduction products are separated into the individualalpha and beta isomers by methods known in the art for the separation ofanalogous pairs of known isomeric prostanoic acid derivatives. See, forexample, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem.240, 457 (1965), and Green et al., J. Lipid Research 5, 117 (1964).Especially preferred as separation methods are partition chromatographicprocedures, both normal and reversed phase, preparative thin layerchromatography, and countercurrent distribution procedures.

The various PGA-type oxa-phenylene compounds encompassed by formulasXXIV-XXVII and XXXIV are prepared by acidic dehydration of thecorresponding PGE type compounds encompassed by formulas XVI-XIX andXXXII. For example, acidic dehydration of3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ gives3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁.

These acidic dehydrations are carried out by methods known in the artfor acidic dehydrations of known prostanoic acid derivatives. See, forexample, Pike et al., Proc. Nobel Symposium II, Stockholm (1966),Interscience Publishers, New York, pp. 162-163 (1967); and BritishPatent Specification No. 1,097,533. Alkanoic acids of 2 to 6 carbonatoms, inclusive, especially acetic acid, are preferred acids for thisacidic dehydration. Dilute aqueous solutions of mineral acids, e.g.,hydrochloric acid, especially in the presence of a solubilizing diluent,e.g., tetrahydrofuran, are also useful as reagents for this acidicdehydration, although these reagents may cause partial hydrolysis of anester reactant.

The various PGB-type oxa-phenylene compounds encompassed by formulasXXVIII-XXXI and XXXV are prepared by basic dehydration of thecorresponding PGE type compounds encompassed by formulas XVI-XIX andXXXII, or by contacting the corresponding PGA type compounds encompassedby formulas XXIV-XXVII and XXXIV with base. For example, both3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ and3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ give3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGB₁ on treatment with base.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238,3555 (1963). The base is any whose aqueous solution has pH greater than10. Preferred bases are the alkali metal hydroxides. A mixture of waterand sufficient of a water-miscible alkanol to give a homogeneousreaction mixture is suitable as a reaction medium. The PGE-type orPGA-type compound is maintained in such a reaction medium until nofurther PGB-type compound is formed, as shown by the characteristicultraviolet light absorption near 278 mμ for the PGB type compound.

The various transformations of PGE-type oxa-phenylene compounds offormulas XVI-XIX to the corresponding PGF.sub.α, PGF.sub.β, PGA and PGBtype oxa-phenylene compounds are shown in Chart A, wherein G, Q, R₁, and˜ are as defined above, wherein E' is --CH₂ CHR₉ -- or trans--CH=CR₉ --,wherein R₂₆ and R₉ are hydrogen or alkyl of one to 4 carbon atoms,inclusive, and wherein J' is ##SPC18##

wherein V is C_(g) H_(2g), cis or trans ##EQU8## or --C.tbd.C--C_(j)H_(2j) wherein C_(g) H_(2g), C_(j) H_(2j), C_(p) H_(2p), R₃, and R₄ areas defined above, and wherein C_(q) H_(2q) represents alkylene of one to6 carbon atoms, inclusive, with one, 2, or 3 carbon atoms between --O--and --COOR₁.

The various 13,14-dihydro-PGE₁, -PGF₁, -PGA₁, and -PGB₁, typeoxa-phenylene compounds encompassed by formulas XIX, XXIII, XXVII, andXXXI are prepared by carbon-carbon double bond reduction of thecorresponding PGE, PGF, PGA, and PGB type compound containing a transdouble bond in the hydroxy-containing side chain. A cis or trans doublebond or a triple bond can also be present in the carboxy-terminated sidechain of the unsaturated reactant, and will be reduced at the same timeto --CH₂ CH₂ --. For example,13,14-dihydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ is producedby reduction of 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁,3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₂, or5,6-dehydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₂.

These reductions are carried out by reacting with the unsaturated PGE,PGF.sub.α, PGF.sub.β, PGA, or PGB type oxa-phenylene compound withdiimide, following the general procedure described by van Tamelen etal., J. Am. Chem. Soc. 83, 3725 (1961). ##SPC19##

See also Fieser et al., "Topics in Organic Chemistry," ReinholdPublishing Corp., New York, pp. 432-434 (1963) and references citedtherein. The unsaturated acid or ester reactant is mixed with a saltazodiformic acid preferably an alkali metal salt such as disodium ordipotassium salt, in the presence of an inert diluent, preferably alower alkanol such as methanol or ethanol, and preferably in the absenceof substantial amounts of water. At least one molecular equivalent ofthe azodiformic acid salt is used for each multiple bond equivalent ofthe unsaturated reactant. The resulting suspension is then stirred,preferably with exclusion of oxygen, and the mixture is made acid,advantageously with a carboxylic acid such as acetic acid. When areactant wherein R₁ is hydrogen is used, the carboxylic acid reactantalso serves to acidify an equivalent amount of the azodiformic acidsalt. A reaction temperature in the range of about 10° to about 40° C.is usually suitable. Within that temperature range, the reaction isusually complete within less than 24 hours. The desired dihydroproduction is then isolated by conventional methods, for example,evaporation of the diluent, followed by separation from inorganicmaterials by solvent extraction.

In the case of the oxa-phenylene unsaturated PGE, PGF.sub.α, andPGF.sub.β type reactants, the reductions to the correspondingdihydro-PGE₁, dihydro-PGF₁ .sub.α, and dihydro-PGF₁ .sub.α typeoxa-phenylene compounds are also carried out by catalytic hydrogenation.For that purpose, palladium catalysts, especially on a carbon carrier,are preferred. It is also preferred that the hydrogenation be carriedout in the presence of an inert liquid diluent, for example, methanol,ethanol, dioxane, ethyl acetate, and the like. Hydrogenation pressuresranging from about atmospheric to about 50 p.s.i., and hydrogenationtemperatures ranging from about 10° to about 100° C. are preferred. Theresulting dihydro product is isolated from the hydrogenation reactionmixture by conventional methods, for example, removal of the catalyst byfiltration or centrifugation, followed by evaporation of the solvent.

Diimide reductions and catalytic hydrogenations to produce the variousnovel formula XIX, XXIII, XXVII, and XXXI 13,14-dihydro compounds ofthis invention from the corresponding PGE, PGF, PGA and PGB typeoxa-phenylene compounds of the PG₁, PG₂, trans-5,6-dehydro-PG₁, and5,6-dehydro-PG₂ series are shown in Chart B. G, J', Q, R₁, R₉, R₂₆, and˜ are as defined above, and L' is ##SPC20##

wherein C_(g) H_(2g), C_(p) H_(2p), and C_(q) H_(2q) are as definedabove.

The oxa-phenylene compounds of the PGE₂, PGF₂, PGA₂, and PGB₂ typewherein the carbon-carbon double bond in the carboxy-terminated sidechain is in cis configuration are prepared by reduction of thecorresponding acetylenic oxa-phenylene compounds, i.e., those with acarbon-carbon triple bond in place of said carbon-carbon double bond.For that purpose, there are used any of the known reducing agents whichreduce an acetylenic linkage to a cis-ethylenic linkage. Especiallypreferred for that purpose are diimide, or hydrogen and a catalyst, forexample, palladium (5%) on barium sulfate, especially in the presence ofpyridine. See Fieser et al., "Reagents for Organic Synthesis," pp.566-567, John Wiley and Sons, Inc., New York, N.Y. (1967). ##SPC21##

These reductions are shown in Chart C, wherein G, Q, R₁, R₉, R₂₆, and ˜are as defined above, and M' is ##SPC22##

wherein C_(j) H_(2j), C_(p) H_(2p), and C_(q) H_(2q) are defined above.These oxa-phenylene cis compounds of the PGE₂, PGF₂.sub.α, PGF₂.sub.β,PGA₂, and PGB₂ type are also prepared as described hereinafter.

The oxa-phenylene PGE-type compounds of formulas XVI-XIX except whereinR₁ is hydrogen, and the oxa-phenylene PGA-type compounds of formulasXXIV-XXVII except wherein R₁ is hydrogen, are prepared by the series ofreactions shown in Chart D, wherein G, J', R₂, R₉, and R₂₆ are asdefined above; G' is the same as G except that T is replaced by T',wherein T' is the same as T above except that R₉ is not hydrogen; R₁₀ isthe same as the above definition of R₁ except that R₁₀ does not includehydrogen; R₁₁ and R₁₂ are alkyl of one to 4 carbon atoms, inclusive; R₁₃is alkyl of one to 5 carbon atoms, inclusive; and ˜ indicates attachmentof --CHR₂₆ --J'--COOR₁₀ to the cyclopentane ring in alpha or betaconfiguration, and attachment of the moiety to the cyclopropane ring inexo or endo configuration.

The oxa-phenylene PGE₁ -type compounds of formula XVI, the oxa-phenylene5,6-dehydro-PGE₂ type compounds of formula XVIII, the oxa-phenylene PGA₁-type compounds of the formula XXIV and the oxa-phenylene5,6-dehydro-PGA₂ type compounds of formula XXVI are also prepared by theseries of reactions shown in Chart E, wherein G, G', R₂, R₉, R₁₀, R₁₃,and R₂₆ are as defined above; Z' is L' or --C.tbd.C--M'-- wherein L' andM' are as defined above; and ˜ indicates attachment of --CHR₂₆--Z'--COOR₁₀ to the cyclopentane ring in alpha or beta configuration,and attachment of the moiety to the cyclopropane ##SPC23## ##SPC24####SPC25##

cyclopropane ring in ex or endo configuration.

It should be observed regarding the series of reactions shown in ChartsD and E, that the reactions starting with glycol XXXVIII in Chart D aresimilar to the reactions starting with glycol XLV in Chart E. The onlydifferences here are the definitions of the divalent moieties J' (ChartD) and Z' (Chart E). J' includes saturated, cis and trans ethylenic, andacetylenic divalent moieties. Z' is limited to the saturated andacetylenic divalent moieties encompassed by J'. In other words, finaloxa-phenylene PGE-type compounds of formula XL (Chart D) encompasscompounds of formulas XVI to XVIII. Final oxa-phenylene PGA-typecompounds of formula XLI (Chart D) encompass compounds of formulas XXIVto XXVI. On the other hand, final oxa-phenylene PGE-type compounds offormula XLVII (Chart E) encompass only compounds of formulas XVI andXVIII, and final oxa-phenylene PGA-type compounds of formula XLVIII(Chart E) encompass only compounds of formula XXIV and XXVI.

As will subsequently appear, an acetylenic intermediate of formulasXXXVII, XXXVIII, or XLV is transformed by step-wise reduction to thecorresponding cis or trans ethylenic intermediates of formulas XXXVII orXXXVIII; and an acetylenic intermediate of formulas XXXVII, XXXVIII, orXLV or a cis or trans ethylenic intermediate of formulas XXXVII orXXXVIII is transformed by reduction to the corresponding saturatedintermediate of formulas XXVII, XXXVIII, or XLV.

The initial bicyclo-ketone reactant of formula XLIII in Chart E is alsoused as an initial reactant to produce the initial bicyclo-ketone cyclicketal reactant of formula XXXVI in Chart D. The following reactions willproduce cyclic ketal XXXVI, wherein THP is tetrahydropyranol, and φisphenyl: ##SPC26##

The bicyclo-ketone reactant of formula XLIII exists in four isomericforms, exo and endo with respect to the attachment of the --CR₉ =CR₂ Gmoiety, and cis and trans with respect to the double bond in that samemoiety. Each of those isomers separately or various mixtures thereof areused as reactants according to this invention to produce substantiallythe same final oxa-phenylene PGE or PGA type product mixture.

The process for preparing either the exo or endo configuration of theformula-XLIII bicyclo-ketone is known to the art. See. U.S. Pat. No.3,776,940 and Belgian Pat. No. 702,477, Derwent Farmdoc No. 30,905.

See West Germany Offenlegungsschrift No. 1,937,912; reprinted in FarmdocComplete Specifications, Book No. 14, No. 6869 R, Week R₅, Mar. 18,1970.

In said U.S. Pat. No. 3,776,940 a reaction sequence capable of formingexo ketone XLIII is as follows: The hydroxy of 3-cyclopentenol isprotected, for example, with a tetrahydropyranyl group. Then adiazoacetic acid ester is added to the double bond to give an exo-endomixture of a bicyclo[3.1.0]hexane substituted at 3 with the protectedhydroxy and at 6 with an esterified carboxyl. The exo-endo mixture istreated with a base to isomerize the endo isomer in the mixture to moreof the exo isomer. Next, the carboxylate ester group at 6 is transformedto an aldehyde group or ketone group, ##EQU9## wherein R₉ is as definedabove. Then, said aldehyde group or said keto group is transformed bythe Wittig reaction, in this case to a moiety of the formula --CR₉ =CR₂G which is in exo configuration relative to the bicyclo ring structure.Next, the protective group is removed to regenerate the 3-hydroxy whichis then oxidized, for example, by the Jones reagent, i.e., chromic acid(see J. Chem. Soc. 39 (1946)), to give said exo ketone XLIII.

Separation of the cis-exo and trans-exo isomers of XLIII is described insaid U.S. Pat. No. 3,776,940. However, as mentioned above, thatseparation is usually not necessary since the cis-trans mixture isuseful as a reactant in the next process step.

The process described in said U.S. Pat. No. 3,776,940 for producing theexo form of bicyclo-ketone XLIII uses, as an intermediate, the exo formof a bicyclo [3.1.0]-hexane substituted at 3 with a protected hydroxy,e.g., tetrahydropyranyloxy, and at 6 with an esterified carboxyl. Whenthe corresponding endo compound is substituted for that exointermediate, the process in said Offenlegungsschrift No. 1,937,912leads to the endo form of bicyclo-ketone XLIII. That end compound to beused has the formula: ##SPC27##

Compound LII is prepared by reactingendo-bicyclo[3.1.0]-hex-2-ene-6-carboxylic acid methyl ester withdiborane in a mixture of tetrahydrofuran and diethyl ether, a reactiongenerally known in the art, to giveendo-bicyclo[3.1.0]-hexane-3-ol-6-carboxylic acid methyl ester which isthen reacted with dihydropyran in the presence of a catalytic amount ofPOCl₃ to give the desired compound. This is then used as described insaid German Offenlegungsschrift No. 1,937,912 to produce the endo formof bicyclo-ketone XLIII.

As for exo XLIII, the above process produces a mixture of endo-cis andendo-trans compounds. These are separated as described for theseparation of exo-cis and exo-trans XLIII, but this separation isusually not necessary since, as mentioned above, the cis-trans mixtureis useful as a reactant in the next process step.

In the processes of said U.S. patent and said Offenlegungsschrift,certain organic halides, e.g., chlorides and bromides, are necessary toprepare the Wittig reagents used to generate the generic moiety, --CR₉=CR₂ G of bicyclo-ketone XLIII. These organic chlorides and bromides##EQU10## are known in the art or can be prepared by methods known inthe art.

To illustrate the availability of these organic chlorides consider firstthe above-described oxa-phenylene PGE-type compounds of formulas XVI toXIX wherein R₂ is hydrogen and G is either (1) alkyl of one to 10 carbonatoms, inclusive, substituted with zero, one, 2, or 3 fluoro or##SPC28##

wherein C_(t) H_(2t) represents a valence bond or alkylene of one to 10carbon atoms, inclusive, substituted with zero, one, or 2fluoro, withone to 7 carbon atoms, inclusive, between ##EQU11## and the ring,wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₆, wherein R₆ is hydrogen or alkyl of one to 4carbon atoms, inclusive, and s is zero, one, 2, or 3, with the provisothat not more than two T's are other than alkyl.

For those products wherein G is alkyl of two to 10 carbon atoms,substituted with 0-3 fluoro atoms, there are available the monohalohydrocarbons, e.g., bromo-(or chloro-) -ethane, -propane, -pentane,-octane, and -decane; and the monohalofluorohydrocarbons, e.g., CH₂ FCH₂Br, CHF₂ CH₂ Cl, CF₃ CH₂ Br, F(CH₂)₃ Br, CH₃ CF₂ CH₂ Cl, CF₃ (CH₂)₂ Br,F(CH₂)₄ Cl, CH₃ CF₂ CH₂ CH₂ Cl, C₄ H₉ CFHCH₂ Br, CF₃ (CH₂)₃ Cl, CF₃(CH₂)₂ BrCH₃, CH₂ F(CH₂)₄ Cl, C₂ H₅ CF₂ (CH₂)₂ Cl, CF₃ (CH₂)₄ Cl, CH₃(CH₂)₄ CF₂ (CH₂)₂ CH₂ Cl, and CH₃ (CH₂)₃ CF₂ (CH₂)₃ CH₂ Cl, as describedin "Aliphatic Fluorine Compounds," A. M. Lovelace et al., Am. Chem. Soc.Monograph Series, 1958, Reinhold Publ. Corp. Those halides not availableare prepared by methods known in the art by reacting the correspondingprimery alcohol G--CH₂ OH with PCl₃ PBr₃, or any of the otherhalogenating agents useful for this purpose. Available alcohols includeCH₂ CH(CF₃)CH₂ OH, (CH₃)₂ CHCH₂ CH₂ OH, (CH₃)₃ CCH₂ OH, CF₃ CH(CH₃)CH₂CH₂ OH, for example. For those halides of the formula G--CH₂ --Halwherein Hal is chloro or bromo, G is R₂₇ --(CH₂)_(h) --, h being one, 2,3, or 4, and R₂₇ being isobutyl, tert-butyl, 3,3-difluorobutyl,4,4-difluorobutyl, or 4,4,4-trifluorobutyl, the intermediate alcoholsare prepared as follows.

In the case of R₂₇ being isobutyl or tert-butyl, known alcohols areconverted to bromides, thence to nitriles with sodium cyanide, thence tothe corresponding carboxylic acids by hydrolysis, and thence to thecorresponding primary alcohols by reduction, e.g., with lithium aluminumhydride, thus extending the carbon chain one carbon atom at a time untilall primary alcohols are prepared.

In the case of R₂₇ being 3,3-difluorobutyl, the necessary alcohols areprepared from keto carboxylic acids of the formula, CH₃ --CO--(CH₂)_(r)--COOH, wherein r is 2, 3, 4, 5, or 6. All of those acids are known. Themethyl esters are prepared and reacted with sulfur tetrafluoride toproduce the corresponding CH₃ --CF₂ --(CH₂)_(r) --COOCH₃ compounds,which are then reduced with lithium aluminum hydride to CH₃ --CF₂--(CH₂)_(r) --CH₂ OH. These alcohols are then transformed to the bromideor chloride by reaction with PBr₃ or PCl₃.

In the case of R₂₇ being 4,4-difluorobutyl, the initial reactants arethe known dicarboxylic acids, HOOC--(CH₂)_(f) --COOH, wherein f is 3, 4,5, 6, or 7. These dicarboxylic acids are esterified to CH₃OOC--(CH₂)_(f) --COOCH₃ and then half-saponified, for example withbarium hydroxide, to give HOOC--(CH₂)_(f) --COOCH₃. The free carboxylgroup is transformed first to the acid chloride with thionyl chlorideand then to an aldehyde by the Rosenmund reduction. Reaction of thealdehyde with sulfur tetrafluoride then gives CHF₂ --(CH₂)_(f) --COOCH₃which by successive treatment with lithium aluminum hydride and PBr₃ orPCl₃ gives the necessary bromides or chlorides, CHF₂ --(CH₂)_(f) --CH₂Br or CHF₂ --(CH₂)_(f) --CH₂ Cl.

In the case of R₂₇ being 4,4,4-trifluorobutyl, aldehydes of the formulaCH₃ OOC--(CH₂)_(f) --CHO are prepared as described above. Reduction ofthe aldehyde with sodium borohydride gives the alcohol CH₃OOC--(CH₂)_(f) --CH₂ OH. Reaction with PBr₃ or PCl₃ then gives CH₃OOC--(CH₂)_(f) -CH₂ --Hal. Saponification of that ester gives thecarboxylic acid which by reaction with sulfur tetrafluoride gives thenecessary CF₃ --(CH₂)_(f) --CH₂ Br or CF₃ --(CH₂)_(f) --CH₂ --Cl.

For the above reactions of SF₄, see U.S. Pat. No. 3,211,723 and J. Org.Chem. 27, 3164 (1962).

For those products wherein R₂ is hydrogen and G is ##SPC29##

the halides necessary to prepare those compounds, if not readilyavailable, are advantageously prepared by reacting the correspondingprimary alcohol, ##SPC30##

with PCl₃, PBr₃, HBr, or any of the other halogenating agents known inthe art to be useful for this purpose. Some of the readily availablehalides are shown in Table I wherein s, T, and t of the formula for theintermediate halides are as defined above, and Hal is chloro, bromo, oriodo. Thus, compound No. 1 of Table I is represented by the formulawherein s and t are zero, and Hal is chloro, i.e. ##SPC31##

namely α-chlorotoluene or benzyl chloride; compound No. 8 of Table I isrepresented by the formula wherein s is zero, t is 2, and Hal is bromo,i.e. ##SPC32##

namely 1-bromo-3-phenylpropane or 3-bromopropylbenzene; and compound No.63 of Table I represented by the formula wherein s is 3, T is methyl inthe 2-, 4- and 5-positions with respect to the C_(t) H_(2t)substitution, t is 2, and Hal is bromo, i.e., ##SPC33##

namely 1 -(3-bromopropyl)-2,4,5-trimethylbenzene.

                  TABLE I                                                         ______________________________________                                        Intermediate Halides                                                          represented by the formula                                                    No.        s       T             t      Hal                                   ______________________________________                                        1          0       --            0      Cl                                    2          0       --            0      Br                                    3          0       --            0      l                                     4          0       --            1      Cl                                    5          0       --            1      Br                                    6          0       --            1      l                                     7          0       --            2      Cl                                    8          0       --            2      Br                                    9          0       --            2      l                                     10         0       --            3      Cl                                    11         0       --            3*     Cl                                    12         0       --            3      Br                                    13         0       --            4      Cl                                    14         1       2--CH.sub.3   0      Cl                                    15         1       2--C.sub.2 H.sub.5                                                                          0      Cl                                    16         1       4--C.sub.2 H.sub.5                                                                          0      Cl                                    17         1       2--CF.sub.3   0      Cl                                    18         1       4--OCH.sub.3  0      Cl                                    19         1       3--CH.sub.3   0      Br                                    20         1       4--CH.sub.3   0      Br                                    21         1       4--C.sub.5 H.sub.11                                                                         0      Br                                    22         1       4--Cl         0      Br                                    23         1       2--CF.sub.3   0      Br                                    24         1       3--CF.sub.3   0      Br                                    25         1       4--CH.sub.3   0      l                                     26         1       4--F          1      Cl                                    27         1       3--Cl         1      Br                                    28         1       4--Cl         1      Br                                    29         1       4--F          1      Br                                    30         1       2--Cl         2      Br                                    31         1       3--Cl         2      Br                                    32         1       4--Cl         2      Br                                    33         1       4--F          3*     Br                                    34         1       2--Cl         4      Br                                    35         1       2--CH.sub.3   0      Cl                                                       4--CH.sub.3                                                36         2       2--CH.sub.3   0      Cl                                                       5--CH.sub.3                                                37         2       2--CH.sub.3   0      Cl                                                       6--CH.sub.3                                                38         2       3--CH.sub.2   0      Cl                                                       4--CH.sub.3                                                39         2       2--CH.sub.3   0      Cl                                                       4--Cl                                                      40         2       2--CH.sub.3   0      Br                                                       5--CH.sub.3                                                41         2       2--CH.sub.3   0      Br                                                       6--CH.sub.3                                                42         2       3--CH.sub.3   0      Br                                                       5--t--butyl                                                43         2       3--CH.sub.3   0      Br                                                       4--Cl                                                      44         2       2--CH.sub.3   0      Br                                                       3--Br                                                      45         2       3--OCH.sub.3  0      Cl                                                       4--OCH.sub.3                                               46         2       3--OCH.sub.3  0      Cl                                                       5--OCH.sub.3                                               47         2       3--OCH.sub.3  0      Br                                                       5--OCH.sub.3                                               48         2       2--CH.sub.3   1      Cl                                                       4--CH.sub.3                                                49         2       2--CH.sub.3   1      Br                                                       4--CH.sub.3                                                50         2       3--CH.sub.3   1      Br                                                       4--CH.sub.3                                                51         2       3--OCH.sub.3  1      Br                                                       4--OCH.sub.3                                               52         2       3--OCH.sub.3  1      Br                                                       5--OCH.sub.3                                               53         2       3--OCH.sub.3  1      l                                                        4--OCH.sub.3                                               54         2       3--OCH.sub.3  2      Br                                                       4--OCH.sub.3                                               55         2       3--OCH.sub.3  2      Br                                                       5--OCH.sub.3                                               56         2       3--OCH.sub.3  4      Br                                                       5--OCH.sub.3                                               57         3       2--CH.sub.3   0      Cl                                                       4--CH.sub.3                                                                   5--CH.sub.3                                                58         3       2--CH.sub.3   0      Cl                                                       4--CH.sub.3                                                                   6--CH.sub.3                                                59         3       4--CH.sub.3   0      Cl                                                       2--OCH.sub.3                                                                  5--OCH.sub.3                                               60         3       2--CH.sub.3   0      Br                                                       3--CH.sub.3                                                                   6--CH.sub.3                                                61         3       2--CH.sub.3   0      Br                                                       4--CH.sub.3                                                                   6--CH.sub.3                                                62         3       2--CH.sub.3   0      Br                                                       3--OCH.sub.3                                                                  6--OCH.sub.3                                               63         3       2--CH.sub.3   2      Br                                                       4--CH.sub.3                                                                   5--CH.sub.3                                                ______________________________________                                        --CH--                                                                        *-branched|                                                          Et                                                                        

Next, considering the intermediate halides for producing oxa-phenylenePGE-type compounds of formulas XIII to XVI wherein R₂ is alkyl of one to4 carbon atoms, inclusive (A), and G is either of the two types (1) or(2) above, these organic chlorides and bromides, ##EQU12## are known tothe art or can be prepared by methods known in the art.

For type A-(1) above, i.e. wherein R₂ is alkyl and G is alkyl of one to10 carbon atoms and 0-3 fluoro atoms, there are available suchmonohalofluorohydrocarbons as CHF₂ CHClCH₃, CF₃ CHBrCH₃, CF₃ CH₂CHBrCH₃, CH₃ CF₂ CHClCH₃, CF₃ CHClC₂ H₅, and C₂ H₅ CF₂ CHClCH₃, forexample. Those not readily available are prepared from the correspondingsecondary alcohol ##EQU13## wherein R₂ is as defined above, with PCl₃,PBr₃, or any of the other halogenating agents known in the art to beuseful for this purpose. Such alcohols include, for example, CH₂FCH(OH)CH₂ F, CF₃ (CH₂)₂ CH(OH)CH₃, CF₃ CH(OH)(CH₂)CH₃, CF₃ CH(OH)(CH₂)₃CH₃, CF₃ CH(OH)C(CH₃)₃, and CF₃ CH(OH)(CH₂)₅ CH₃. For those halides ofthe formula G--CHR₂ --Hal, wherein G is R₂₇ --(CH₂)_(h) --, using thedefinitions of Hal, h, R₂, and R₂₇ above, the intermediate alcohols areprepared as follows.

In the case of R₂₇ being isobutyl or tert-butyl, lower molecular weightprimary alcohols are transformed to the corresponding longer-chaincarboxylic acids and thence to the corresponding secondary alcohols bypreparing the intermediate ketones, ##EQU14## by known procedures, forexample G--COCl + (R₂)₂ Cd, thereafter reducing the ketone to thesecondary alcohol with sodium borohydride.

In the case of R₂₇ being 3,3-difluorobutyl, the procedure describedabove is applicable to converting CH₃ --CF₂ --(CH₂)₂ --COOCH₃ describedabove to ##EQU15## These alcohols are then transformed to the bromide orchloride by reaction with PBr₃ or PCl₃.

In the case of R₂₇ being 4,4-difluorobutyl, the corresponding secondaryalcohols are prepared as described above, using intermediates preparedfor the primary alcohols of this type above.

In the case of R₂₇ being 4,4,4-trifluorobutyl, corresponding secondaryalcohols are prepared by transforming CH₃ OOC--(CH₂)_(f) --CHO to CH₃OOC--(CH₂)_(f) --C(R₂)O by known methods and then proceeding with thatketone as described above for the corresponding aldehyde.

For type A-(2) halides, i.e. R₂ is alkyl and G is ##SPC34##

some of the readily available halides are shown in Table II. Thus,compound No. 1 of Table II is represented by the formula wherein s=0, R₂=methyl, t=0, and Hal=Cl, i.e. ##SPC35##

namely (1-chloroethyl)benzene; and compound No. 13 of Table II isrepresented by the formula wherein s=2, T=methyl, R₂ =methyl, t=1, andHal=Br, i.e. ##SPC36##

namely 4-(2-bromopropyl)-o-xylene or1-(2-bromopropyl)3-methyl-4-methylbenzene.

                  TABLE II                                                        ______________________________________                                        Intermediate Halides                                                          represented by the Formula                                                    Hal--CH--C.sub.t H.sub.2t --                                                  |                                                                    R.sub.2                                                                       No.      s      T          R.sub.2   t   Hal                                  ______________________________________                                        1        0      --         CH.sub.3  0   Cl                                   2        0      --         C.sub.2 H.sub.5                                                                         0   Cl                                   3        0      --         C.sub.2 H.sub.5                                                                         0   Br                                   4        0      --         CH.sub.3  0   l                                    5        0      --         CH.sub.3  1   Cl                                   6        0      --         n--C.sub.3 H.sub.7                                                                      1   Cl                                   7        0      --         CH.sub.3  1   Br                                   8        0      --         C.sub.2 H.sub.5                                                                         2   Cl                                   9        1      4--C.sub.2 H.sub.5                                                                       CH.sub.3  0   Cl                                   10       1      4--F       CH.sub.3  0   Cl                                   11       1      4--Cl      C.sub.2 H.sub.5                                                                         0   Br                                   12       1      4--F       C.sub.2 H.sub.5                                                                         0   Br                                   13       2      3--CH.sub.3                                                                              CH.sub.3  1   Br                                                   4--CH.sub.3                                                   14       2      3--OCH.sub.3                                                                             CH.sub.3  1   Br                                                   4--OCH.sub.3                                                  15       2      2--OCH.sub.3                                                                             CH.sub.3  1   Br                                                   6--OCH.sub.3                                                  ______________________________________                                    

Other intermediate halides of the general formula ##SPC37##

may be obtained from the secondary alcohols as discussed above. Thesecondary alcohols, wherein R₂ is alkyl, are prepared by transformingthe --COOH of the corresponding carboxylic acid, ##SPC38##

to a ketone by known procedures, e.g. by way of acyl chloride and adialkylcadmium. Reduction of the ketone with sodium borohydride thenyields the secondary alcohol, ##SPC39##

Hydroxyl groups on the aromatic ring are suitably protected during thesereactions by first forming the corresponding tetrahydropyranyl etherswith dihydropyran; the hydroxyl groups are restored by mild acidhydrolysis as is well known in the art.

In the case of C_(t) H_(2t) substituted with one or 2 fluoro atoms,there are a number of routes of the intermediate halides. Thecorresponding alcohols, for example β-fluorophenethyl alcohol,β-fluoro-α-methyl-phenethyl alcohol, β-fluoro-α,β-dimethyl-phenethylalcohol and the like, are reacted with PCl₃, PBr₃ or HBr to form thehalide. Alternatively, the carboxylic acid having one less carbon atomin the chain than the desired intermediate halide, i.e. ##SPC40##

where g = t-1, is converted by a series of known methods to the2,2-difluorohalide. Thus, the free carboxyl group is transformed firstto the acid chloride with thionyl chloride and thence by way of thenitrile to the α-keto-acid. The carboxyl group is reduced to the alcoholwith diborane and then converted to the α-keto halide. Finally, byreaction of the keto group with sulfur tetrafluoride, there is obtained##SPC41##

As mentioned above, formula XVI-to-XXXI compounds with an alpha-fluorosubstituent in a straight chain 3-to-7-carbon G, i.e., G being--CHF--(CH₂)_(a) --CH₃ wherein a is one, 2, 3, 4, or 5, representembodiments among the novel oxa-phenylene compounds of this invention.Among those, for example, is3-oxa-16-fluoro-3-7-inter-m-phenylene-4,5,6-trinor-PGE₁. Theformula-XLIII bicyclo-ketones necessary to produce those mono-fluorocompounds are advantageously prepared by reacting either of theabove-mentioned bicyclo-aldehydes, exo or endo, with a Wittig reagentprepared from CH₃ --CH₂) a-- CO--CH₂ --Br and triphenylphospine. Thealdehyde group is thereby transformed to ##EQU16## The resultingunsaturated ketone is reduced to the corresponding ##EQU17## compound.Then --OH in that group is replaced with fluoro by known methods, forexample, directly by reaction with 2-chloro-1,1,2-trifluorotriethylamineor indirectly, for example, by transforming the hydroxy to tosyloxy ormesyloxy, and reacting the resulting compound with anhydrous potassiumfluoride in diethylene glycol. Similarly, the oxa-phenylene PG-typecompounds wherein G is ##SPC42##

having an alpha-fluoro substituent on the carbon adjacent to thehydroxy-substituted carbon (C-15 in PGE₁) represent preferredembodiments of this invention. In preparing the formula-XLIIIbicyclo-ketone intermediates, there is used a Wittig reagent preparedfrom ##SPC43##

and triphenylphosphine. Following the steps above, the resultingunsaturated ketone containing the moiety ##SPC44##

is reduced to the corresponding secondary alcohol. The --OH in thatgroup is replaced by fluoro by known methods.

Another preference mentioned above is that the 1-position of G in theformula XVI-to-XXXI compounds be mono- or di-substituted with alkyl ofone to 4 carbon atoms, particularly methyl or ethyl. In the steps of thesynthesis shown in Charts D and E, G is then G'" --CR₂₁ R₂₂ -- whereinR₂₁ and R₂₂ are methyl or ethyl and G'" is preferably alkyl of 2 to 6carbon atoms or ##SPC45##

wherein k is zero, one, 2, or 3. Thus in preparing the formula-XLIIIintermediate olefin, a Wittig reagent is prepared from a halo compoundof the general formula G'" --CR₂₁ R₂₂ --CR₂ H--Hal wherein Hal is chloroor bromo. These compounds are known in the art or can be prepared bymethods known in the art, including those methods described above.

For example, when G'" is CH₃ (CH₂)₃ --, R₂ and R₂₁ are hydrogen, and R₂₂is methyl, there is employed 1-bromo(or -chloro)-2-methylhexane. If thehalo compound is not available, the corresponding carboxylic acid istransformed to the alcohol and thence to the halide. Thus,2,2-diethylvaleric acid yields 1-bromo-2,2-diethylpentane, wherein G'"is CH₃ (CH₂)₂ --, R₂ is hydrogen, and R₂₁ and R₂₂ are ethyl.

2-Ethylhexanoic acid yields 3-chloromethylheptane, wherein G'" is CH₃(CH₂)₃ --, R₂ and R₂₁ are hydrogen, and R₂₂ is ethyl.2-Ethyl-2-methylhexanoic acid yields 3-bromo-methyl-3-methylheptane,wherein G'" is CH₃ (CH₂)₃ --, R₂ is hydrogen, R₂₁ is methyl, and R₂₂ isethyl. 2-Phenylpropionic acid yields 1-bromo-2-phenylpropane, whereinG'" is phenyl, R₂ and R₂₁ are hydrogen, and R₂₂ is methyl.2-Methyl-2-phenylbutyric acid yields 1-bromo-2-methyl-2-phenylbutane,wherein G'" is phenyl, R₂ is hydrogen, R₂₁ is methyl, and R₂₂ is ethyl.2-Methyl-4-(2,4,5-trimethoxyphenyl)butyric acid yields1-chloro-2-methyl-4-(2,4,5-trimethoxyphenyl)butane, wherein G'" is(2,4,5-trimethoxyphenyl)ethyl, R₂ and R₂₁ are hydrogen, and R₂₂ ismethyl.

Mono-alkyl substituted alkanoic acids useful for preparing the abovehalo intermediates are prepared by alkylation of an α-keto acid, G'"--CO--COOH, e.g. ##SPC46##

(prepared via the acid chloride and thence the nitrile) by means of aGrignard reagent, R₂₂ MgHal for example.

The transformation of bicyclo-ketone-olefin XLIII to glycol LI iscarried out by reacting olefin XLIII with a hydroxylation reagent.Hydroxylation reagents and procedures for this purpose are known in theart. See, for example, Gunstone, Advances in Organic Chemistry, Vol. I,pp. 103-147, Interscience Publishers, New York, N.Y. (1960). Especiallyuseful hydroxylation reagents for this purpose are osmium tetroxide andperformic acid (formic acid plus hydrogen peroxide). Various isomericglycols are obtained depending on such factors as whether olefin XLIIIis cis or trans and endo or exo, and whether a cis or a transhydroxylation reagent is used. These various glycol mixtures can beseparated into individual isomers by silica gel chromatography. However,this separation is usually not necessary, since all isomers ofparticularly glycol are equally useful as intermediates according tothis invention and the processes outlined in Chart D to produce finalproducts of formulas XL and XLI, and then, according to Chart A, B, andC to produce the other final products of this invention.

The transformation of glycol LI to the cyclic ketal of formula XXXVI(Chart D) is carried out by reacting said glycol with a dialkyl ketoneof the formula ##EQU18## wherein R₁₁ and R₁₂ are alkyl of one to 4carbon atoms, inclusive, in the presence of an acid catalyst, forexample potassium bisulfate or 70% aqueous perchloric acid. A largeexcess of the ketone and the absence of water is desirable for thisreaction. Examples of suitable dialkyl ketones are acetone, methyl ethylketone, diethyl ketone, methyl propyl ketone, and the like. Acetone ispreferred as a reactant in this process.

Referring again to Chart D, cyclic ketal XXXVI is transformed to cyclicketal XXXVII by alkylating with an alkylation agent of the formula##EQU19## wherein R₁₀, R₂₆, and J' are as defined above, and Hal ischlorine, bromine, or iodine. Similarly, referring to Chart E, olefinXLIII is transformed to olefin XLIV by alkylating with an alkylationagent of the formula ##EQU20## wherein R₁₀, R₂₆, Z', and Hal are asdefined above.

Any of the alkylation procedures known in the art to be useful foralkylating cyclic ketones with alkyl halides and haloalkanoic esters areused for the transformations of XXXVI to XXXVII and of XLIII to XLIV.See, for example, the above-mentioned Belgian Pat. No. 702,477 forprocedures useful here and used there to carry out similar alkylations,e.g., employing the bicyclo enamines.

For these alkylations, it is preferred that Hal be bromo or iodo. Any ofthe usual alkylation bases, e.g., alkali metal alkoxides, alkali metalamides, and alkali metal hydrides, are useful for this alkylation.Alkali metal alkoxides are preferred, especially tert-alkoxides. sodiumand potassium are preferred alkali metals. Especially preferred ispotassium tert-butoxide. Preferred diluents for this alkylation aretetrahydrofuran and 1,2-dimethoxyethane. Otherwise, procedures forproducing and isolating the desired formula-XXXVII and -XLIV compoundsare within the skill of the art.

These alkylation procedures produce mixtures of alpha and betaalkylation products, i.e. a mixture of formula XXXVII products whereinpart has the --CHR₂₆ --J'--COOR₁₀ moiety attached in alphaconfiguration, and wherein part has that moiety attached in betaconfiguration, or a mixture of the formula-XLIV products with the--CHR₂₆ --Z'--COOR₁₀ moiety in both alpha and beta configurations. Whenabout one equivalent of base per equivalent of formula-XXXVI or -XLIIIketone is used, the alpha configuration usually predominates. Use of anexcess of base and longer reaction times usually result in production oflarger amounts of beta products. These alpha-beta isomer mixtures areseparated at this stage or at any subsequent stage in the multi-stepprocesses shown in Charts D and E. Silica gel chromatography ispreferred for this separation.

The necessary alkylating agents for the above-described alkylations,e.g. compounds of the formulas ##EQU21## are prepared by methods knownin the art. There are four groups of compounds encompassed by these twogenera of alkylating agents.

Alkylating agents of the formula ##EQU22## include compounds of theformulas: ##SPC47##

Alkylating agents of the formula ##EQU23## include the above-listedcompounds of formuls LIII and LIV, and also compounds of the followingformulas ##SPC48##

These alkylating agents of formulas LIII to LVI are accessible to thoseof ordinary skill in the art. In one route, the ##EQU24## compounds areobtained from aldehyde or ketone reactants by a series oftransformations as follows: ##EQU25## For example, methylm-formylphenoxyacetate on reduction with sodium borohydride yieldsmethyl m-(hydroxymethyl)-phenoxyacetate, which in turn is transformed tothe formula-LIX compound, methyl m-(chloromethyl)phenoxyacetate, withthionyl chloride.

Those formula-LVII or formula-LVIII reactants which are not commerciallyavailable are advantageously prepared by adaptation of the Williamsonether syntheses, e.g. employing a hydroxy reactant and ahalo-substituted acid or ester. Thus, the reaction ##SPC49##

wherein Hal is chloro, bromo, or iodo, preferably iodo, proceeds in thepresence of strong base, for example sodium hydride when R₁ is acarbon-containing group, and lithium diisopropyl amide when R₁ ishydrogen. within the definitions of C_(g) H_(2g), C_(p) H_(2p), andC_(q) H_(2q), suitable reactants are readily available or are preparedby methods known to those skilled in the art.

Thus, when R₂₆ is hydrogen, and considering the variations of C_(g)H_(2g) and C_(p) H_(2p), the aldehyde reactants include (o, m, orp)-hydroxybenzaldehyde, (o, m, or p-hydroxyphenyl)acetaldehyde, (o orp)-hydroxyhydrocinnamaldehyde, 4-(o or p-hydroxyphenyl)butyraldehyde,o-(2-hydroxyethyl)-benzaldehyde, and the like. Other aldehyde reactantsare also accessible by methods known to those skilled in the art. Forexample, (o, m, or p-hydroxyethyl)benzaldehydes are obtained from (o, m,or p)-bromostyrene by the series of reactions: ##SPC50##

The reaction with ethylene oxide is carried out on a Grignard reagentprepared from the bromostyrene and magnesium. Substituted ethyleneoxides are used to obtain substituted C_(p) H_(2p) chains, e.g.propylene oxide, 1,2-epoxy-2-methylpropane, 1,2-epoxybutane,1,2-epoxy-2,3-dimethylbutane, and the like. Instead of using ozone toform the aldehyde, hydroxylation and oxidation with osmium tetroxide andperiodic acid are optional (see J. Org. Chem. 21, 478, 1956).

Compounds with C_(g) H_(2g) chains are obtained by replacing

with ##SPC51##

e.g. 1-allyl-4-bromobenzene 1-allyl-2-chlorobenzene, 4-(o, m, orp-chlorophenyl)-1-butene, and the like. Compounds with C_(p) H_(2p)chains are obtained by replacing ethylene oxide with suitable alkylatingagents, e.g. trimethylene oxide, 1,3-epoxybutane,1,3-epoxy-3-methylbutane and the like, or suitable reactions steps.

Other variations of the above reactions and reactants will be apparentto those skilled in the art. Thus, an alkene-substituted phenol iscondensed with a halo-substituted acid or ester and thereaftertransformed as an aldehyde to the halo alkylating agent within the scopeof formula LIX by the following steps: ##SPC52##

Available for this series of reactions are (o, m, or p)-vinylphenol,p-allylphenol, 4-(o, m, or p-hydroxyphenyl)-1-butene, and the like.

Alternatively, a haloalkylphenol is condensed with a halo-substitutedacid or ester by the reaction: ##SPC53##

Available are p-(2-bromoethyl)phenol, p-(3-bromobutyl)-phenol, and thelike.

Considering the halo-substituted acid or ester reactants in the aboveether syntheses and the variations of C_(q) H_(2q), there are a widevariety of reactants available, which will lead to the desiredformula-LIX alkylating agent. For example: ##EQU26## wherein R₂₃ ishydrogen or alkyl of one to 5 carbon atoms, inclusive; Br--(CH₂)₂--COOH, Br--C(CH₃)₂ --COOH, Br--C(C₂ H₅)₂ --COOH, BrC(CH₃)(C₂ H₅)--COOH,Br--CH(CH₃)--CH₂ --COOH, Br--(CH₂)₃)--COOCH₃, Cl--CH(C₂ H₅)--CH₂--COOCH₃, Cl--CH(n--C₃ H₇)--CH₂ --COOCH₃, Br--CH(CH₃)--(CH₂)₂ --COOC₂H₅, Br--CH(CH₃)--CH₂ --CH(CH₃)--COOC₂ H₅, Br--CH(CH₃)--CH(CH₃)--CH₂--COOC₂ H₅, Br--C(CH₃)₂ --CH₂ --CH(CH₃)--COOC₂ H₅, Cl--CH(n--C₄ H₉)--CH₂--COOC₂ H₅, Cl--C(CH₃)₂ --CH₂ --COOC₂ H₅, Br--CH(n--C₂ H₇)--(CH₂)₂--COOH, and Cl--CH(C₂ H₅)--(CH.sub. 2)₂ --COOH are available. Thepreferred iodo reactants are obtained by methods known to those skilledin the art.

When C_(q) H_(2q) has two alkyl groups attached to the ω or ω-1 carbonatom of the halo-substituted acid or ester reactants, it is preferredthat halo be replaced with mesyloxy or tosyloxy prior to the ethersynthesis, and that relative mild bases and reaction conditions be used,for example, potassium tert-butoxide in dimethyl sulfoxide.

In another route to the formula-LIX alkylating agents, the Williamsonether synthesis employs hydroxy-esters or acids of the formula HO--C_(q)H_(2q) --COOR₁ for condensation with halo-substituted reactants asfollows: ##SPC54##

For example, α,α'-dibromo-o-xylene is contacted with ethyl glycolate inthe presence of sodium hydride to yield ethylO-(bromomethyl)-benzyloxyacetate.

Typical halo reactants which are useful for this reaction areα-bromo-(o, m, or p)-chlorotoluene, 1-bromo-(2 or3)-(2-bromoethyl)benzene, 1-(3-bromopropyl)-(1 or 2)-chlorobenzene, and1-(4-bromobutyl)-1-chlorobenzene.

When C_(p) H_(2p) has two alkyl groups attached to the carbon atom towhich Hal is attached, it is preferred that this Hal be replaced withmesyloxy or tosyloxy prior to the ether synthesis and that relativelymild bases and reaction conditions be used.

Considering the hydroxy acid or ester reactants, there are available awide range of suitable compounds within the scope of HO--C_(q) H_(2q)--COOR₁ which will lead to the desired formula-LIX alkylating agent. Forexample: HOCH(CH₃)--COOCH₃, HOC(CH₃)₂ --COOH, HOCH(C₂ H₅)--COOH,HOC(CH₃)(C₂ H₅)--COOH, HO(CH₂)₂ --COOC₂ H₅, HOCH(CH₃)--CH₂ --COOH,HOCH(n--C₃ H₇)--COOH, HOC(n--C₃ H₇)(CH₃)--COOH, HOCH(C₂ H₅)--CH₂ --COOH,HOCH(CH₃)--(CH₂)₂ --COOH, HOCH(n-C₄ H₉)--COOH, HOC(n-C₄ H₉)(CH₃)--COOH,HOCH(n-C₃ H₇)--CH₂ --COOCH₃,HOCH(C₂ H₅)--(CH₂)₂ --COOH, HOCH(n-C₅H₁₁)--COOH, HOCH(n-C₄ H₉)--CH₂ --COOH, HOCH(n-C₃ H₇)--(CH₂)₂ --COOH areavailable.

When a formula-LIX alkylating agent is desired in which there are twoalkyl substituents on both carbon atoms attached to the oxa --O--, it ispreferred that, if the halo-acid route be used, the halo atom on theacid be chloro and that freshly precipitated wet magnesium hydroxide inan inert solvent suspension be used as the base; and if the hydroxy-acidroute be used, the --C_(p) H_(2p) --Hal group is preferrably --C_(p)H_(2p) --Cl. If the hydroxy-acid route is used with --C_(p) H_(2p) --l,silver oxide is used as the base.

The alkylating agents of formulas LIII to LVI are esters. Any of theabove acid forms are readily converted to esters. Variations in R₁₀within the definition of R₁₀ herein are readily made by methods known inthe art. The ester moiety is chosen according to the desired type offinal oxa-phenylene PG-type product.

Formula-LVII aldehyde reactants which lead to the formula LIX alkylatingagents are also obtained by reaction of halo-substituted aldehydes withhydroxy acids or ester reactants. Thus, there are employedo-(bromomethyl)benzaldehyde, p-chlorohydratropaldehyde, and the like.

When R₂₆ is alkyl, the formula-LIX ##EQU27## alkylating agents areprepared from the corresponding reactants wherein R₂₆ is methyl, ethyl,propyl, or butyl, or their isomers. For example m-bromo-α-methylstyrenereacts as follows: ##SPC55##

Typical halo-substituted ketones available for this purpose include (2',3', or 4')-(bromo, chloro, or iodo)-acetophenone, (3' or4')-bromopropiophenone, (3' or 4')-chlorobutyrophenone, and 4'-(bromo orchloro)-valerophenone. Other reactants leading to the R₂₆(alkyl)-substituted formula-LIX alkylating agents are accessible tothose skilled in the art.

Although the above methods are generally useful for preparing alkylatingagents within the scope of formulas ##EQU28## above, there are preferredmethods for preparing the formula-LIV compounds containing the--C.tbd.C--C_(j) H_(2j) -- moiety.

Considering the compounds of the formula ##SPC56##

there is employed as starting material (o, m, or p-)vinylanisole in thefollowing series of transformations: ##SPC57##

Herein, THP represents tetrahydropyranyl and R₂₈ represents ##SPC58##

The reagents and conditions for bringing about these transformations areknown to those skilled in the art. Thus, in step a, reacting first withbromine and then with sodium amide in liquid ammonia yields theacetylenic derivative (see J. Am. Chem. Soc. 56, 2064, 1934). Step butilizes boron tribromide for example. Step c proceeds either withethylene chlorohydrin and a strong base, e.g., NaOH or KOH, followed bydihydropyran in the presence of an acid catalyst, or with thetetrahydropyranyl ether of the chlorohydrin and a strong base. Step dutilizes R₂₆ COCl in the presence of a strong base, e.g., sodium amide,phenyllithium, or sodium triphenylmethane. Alternatively, if R₂₆ isdesirably hydrogen, paraformaldehyde is employed (see J. Am. Chem. Soc.92, 6314 (1970). The reaction in step e is done with a metal hydride,e.g., sodium borohydride. In step f thionyl chloride yields theformula-LX chloro compounds. Finally, in step g the THP moiety isselectively removed by mild hydrolysis in acid medium and the terminal--CH₂ OH moiety is oxidized to --COOH, e.g. with the Jones reagent. Thealkylating agent is converted by known means to an ester, as defined byR₁₀, to yield the desired compounds.

Considering the compounds of the formula ##SPC59##

the above series of transformations are used, except that in step cClCH₂ CH₂ OH is replaced by Cl--C_(q) H_(2q) --CH₂ OH. There areobtained in step f compounds of the formula ##SPC60##

wherein C_(q) H_(2q), Hal, R₂₆ and THP are as defined above. Thereafterthese formula-LXI compounds are transformed as in step g above to thedesired compounds.

Considering the compounds of the formula ##SPC61##

there are employed as starting materials the ar-halostyrenes. These aretransformed by the following steps: ##SPC62##

Thereafter, these formula-LXII compounds are transformed as in step gabove to the desired compounds. In step a, the halo compounds areconverted to a Grignard reagent with magnesium and thence reacted withethylene oxide. In step b, the hydroxy group is converted to --OTHP withdihydropyran, the acetylenic moiety is formed as in step a leading tothe formula-LX compounds above, and the THP moiety removed by mild acidhydrolysis. In step c, the chain is extended by reaction with Hal--CH₂CH₂ OH, preferably the bromo or iodo derivatives, in the presence ofstrong base, e.g., phenyl lithium sodium triphenylmethane, or sodiumhydride. Thereafter, in step d the transformations follow the generalscheme of steps d-f leading to the formula-LX compound to yield theformula-LXII compounds. Transformation as in step g above yields thedesired compounds.

Consdering the compounds of the formula ##SPC63##

the series of transformations in the paragraph immediately preceedingare used, except that in step c Hal--CH₂ CH₂ OH is replaced byHal--C_(q) H_(2q) --CH₂ OH. There are obtained in step d compounds ofthe formula ##SPC64##

These formula-LXIII compounds are transformed as in step g above to thedesired esters.

Considering the compounds of the formula ##SPC65##

there are employed as starting materials anisolyl aliphatic acids, e.g.,anisolylacetic acid, in the following steps: ##SPC66##

In step a, the carboxyl group is reduced with a metal hydride, e.g.lithium aluminum hydride. In step b, where Ts represents thetoluenesulfonyl ("tosyl") moiety, the reaction is carried out withtoluenesulfonyl chloride and pyridine. In step c, the acetylenic moietyis introduced with lithium acetylide (see J. Am. Chem. Soc. 80, 6626,1958) to yield the formula-LXIV intermediates. Subsequent steps in d toform the formula-LXV compounds follow from steps b-f for the formula-LXcompounds above. Finally, the formula-LXV compounds are transformeda sin step g above to the desired esters.

Considering the compounds of the formula ##SPC67##

there are employed as starting materials benzenedialiphatic acids, e.g.,benzenediacetic acid, in the following steps: ##SPC68##

In step a, the carboxyl groups are reduced with a metal hydride, e.g.lithium aluminum hydride. In step b, reaction with toluenesulfonylhalide yields the bistosyl derivative. In step c one tosyloxy group isreplaced by reaction with HO--C_(q) H_(2q) --CH₂ OTHP in the presence ofsodium hydride in an inert solvent, e.g. dimethyl formamide. In step d,the acetylenic moiety is introduced as in forming the formula-LXIVcompounds above. Subsequent steps in e to form the formula-LXVIcompounds follow from steps b-f for the formula-LX compounds above.Finally, the formula-LXVI compounds are transformed as in step g aboveto the desired esters.

Variations in the above formula LX-to-LXVI compounds and theircorresponding ester alkylating agents as to chain length or branching inthe C_(g) H_(2g), C_(j) H_(2j), C_(p) H_(2p), and C_(q) H_(2q) moietiesand as to the identity of R₁ or R₂₆, within the scope of these terms asherein defined, are available to those skilled in the art making use ofthe principles disclosed herein.

Other modifications which are encompassed within this disclosure includethe use of alkylating agents wherein Hal is replaced byhydrocarbonsulfonyl, e.g. tosyl or mesyl (methanesulfonyl) groups.Furthermore, the formula-LX, -LXI, -LXII, -LXIII, -LXV, and -LXVIcompounds are alternatively employed as alkylating agents, instead ofthe corresponding esters, and the alkylated formula-XXXVI and -XLIIIcompounds subsequently converted to the desired formula-XXXVII and -XLIVcompounds by mild hydrolysis to remove the THP moiety, oxidation toconvert the --CH₂ OH moiety to --COOH, and, optionally, esterificationto the desired R₁ identity.

The cis and trans ethylenic alkylating agents of formulas LV and LVIabove are preferably prepared by cis or trans reduction of thecorresponding formula-LIV acetylenic compounds prepared as above, or bycis or trans reduction of any earlier acetylenic intermediate in whichboth ends of the acetylenic bond are substituted, i.e., not hydrogen asin the moiety HC.tbd.C--. Alternatively, this cis or trans reduction iscarried out on any subsequent acetylenic reaction product leading up toand including the final acetylenic alkylating agent of formula LIV.

For these cis reductions of acetylenic bonds, it is advantageous to usehydrogen plus a catalyst which catalyzes hydrogenation of --C.tbd.C--only to cis --CH=CH--. Such catalysts and procedures are well known tothe art. See, for example, Fieser et al., "Reagents for OrganicSyntheses", pp. 566-567; John Wiley and Sons, Inc., New York, N.Y.(1967). Palladium (5%) on barium sulfate, especially in the presence ofpyridine as a diluent, is a suitable catalyst for this purpose.Alternative reagents useful to transform these acetylenic compounds tocis-ethylenic compounds are bis(3-methyl-2-butyl)borane("disiamylborane") and diisobutyl-aluminum hydride.

For trans reductions of the acetylenic bond, except for those compoundscontaining halogen, it is advantageous to use sodium or lithium inliquid ammonia or a liquid alkylamine, e.g., ethylamine. When the moietyHO--CH₂ --C.tbd.C-- is present in the acetylenic compound being reduced,the use of lithium aluminum hydride gives trans reduction of the triplebond. Procedures for these trans reductions are known in the art. See,for example, Fieser et al., above cited, pp. 577, 592-594, and 603, andJ. Am. Chem. Soc. 85, 622 (1963).

The alkylating agents of the formulas ##SPC69##

are available by methods known to those skilled in the art.

Thus, the above-described intermediates within the scope of ##SPC70##

are transformed to the phosphoranes and condensed with halo-substitutedketones of the formula ##EQU29## wherein THP is tetrahydropyranyl, bythe Wittig reaction (Organic Reactions, Vol. 14, p. 270, Wiley, 1965).Mixtures of the cis and trans isomers of formulas LXVII and LXVIII areusually obtained, which are separable by methods known in the art.Higher proportions of the cis isomers are obtained in the presence ofLewis bases; higher proportions of the trans isomers result by employingthe phosphonate modification (D. H. Wadsworth et al., J. Org. Chem. 30,680 (1965)). Thereafter, hydrogen on the terminal carboxyl group isreplaced with R₁₀, THP is replaced with hydrogen, and the terminalhydroxyl group replaced with Hal, for example with PBr₃ or PCl₃.

Alternatively, an intermediate of the formula ##SPC71##

is condensed by the Wittig reaction with a phosphorane or phosphonatederived from ##EQU30## Subsequently, the terminal hydroxy group isreplaced with Hal by suitable reagents, for example PBr₃ or PCl₃.

Concerning the alkylation of the cyclopentane ring, another usefulalkylation procedure utilizes an intermediate enamine. That enamine isprepared by mixing either the formula-XXXVI ketal or the formula-XLIIIolefin ketone with a secondary amine of the formula ##EQU31## whereinR₂₄ and R₂₅ are alkyl or alkylene linked together through carbon oroxygen to form together with a nitrogen a 5 to 7-numbered heterocyclicring. Examples of suitable amines are diethylamine, dipropylamine,dibutylamine, dihexylamine, dioctylamine, dicyclohexylamine,methylcyclohexylamine, pyrrolidine, 2-methylpyrrolidine, piperidine,4-methylpiperidine, morpholine, hexamethylenimine, and the like.

The enamine is prepared by heating a mixture of the formula-XXXVI ketalor the formula-XLIII olefin ketone with an excess of the aminepreferably in the presence of a strong acid catalyst such as an organicsulfonic acid, e.g., p-toluenesulfonic acid, or an inorganic acid, e.g.,sulfuric acid. It is also advantageous to carry out this reaction in thepresence of a water-immiscible diluent, e.g., benzene or toluene, and toremove water by azeotropic distillation as it is formed during thereaction. Then, after water formation ceases, the enamine is isolated byconventional methods.

The enamine is then reacted with a haloester, ##EQU32## to give thedesired formula-XXXVII or -XLIV product. This reaction of the enamine iscarried out by the usual procedures. See "Advances in OrganicChemistry," Interscience Publishers, New York, N.Y., Vol. 4, pp. 25-47(1963) and references cited therein. In addition to halogen, R₂₉ in##EQU33## can also be tosylate, mesylate, and the like. It is especiallypreferred that R₂₉ be bromine or iodine. Dimethylsulfoxide is especiallyuseful as a diluent in the reaction of the enamine with the haloester.

Referring again to Chart D, after alkylation as discussed above, cyclicketal XXXVII is transformed to glycol XXXVIII by reacting the cyclicketal with an acid with pK less than 5. Suitable acids and proceduresfor hydrolyzing cyclic ketals to glycols are known in the art. Suitableacids are formic acid, hydrochloric acid, and boric acid. Especiallypreferred as diluents for this reaction are tetrahydrofuran andβ-methoxyethanol.

Referring again to Chart E, after alkylation as discussed above, olefinXLIV is hydroxylated to glycol XLV. As discussed above, the divalentmoiety --Z'-- includes the moieties ##SPC72##

and ##SPC73##

wherein C_(g) H_(2g), C_(j) H_(2j) and C_(q) H_(2q) are as definedabove. When Z' is ##SPC74##

this hydroxylation of XLIV is carried out as described above for thehydroxylation of olefin XLIII to glycol LI, i.e., with any of the knownreagents and procedures described in Gunstone, above cited. When Z' is##SPC75##

some of the reagents and procedures described by Gunstone tend to attackthe acetylenic linkage as well as the ethylenic linkage of theformula-XLIV olefin. Therefore it is preferred to use a hydroxylationreagent and procedure which attacks the ethylenic linkagepreferentially. For this, it is preferred to carry out hydroxylation ofthese acetylenic formula-XLIV olefins with organic peracids, e.g.,performic acid, peracetic acid, perbenzoic acid, and m-chloro-perbenzoicacid, as described by Gunstone, above cited, pp. 124-130.

As discussed above regarding the hydroxylation of unalkylated olefinXLIII to unalkylated glycol LI, various isomeric glycols are obtained byhydroxylation of the formula-XLIV alkylated olefin. The particularformula-XLV glycol or glycol mixture obtained depends on such factors aswhether the olefin XLIV is cis or trans and endo or exo, and whether acis or a trans hydroxylation takes place. However, all of the isomericformula-XLIV glycols and the various glycol mixtures are equally usefulas intermediates according to this invention and the processes of ChartE to produce final products of formulas XLVII and XLVIII, and thenaccording to Charts A, B, and C, to produce the other final products ofthis invention. Therefore, it is usually not necessary to separateindividual formula-XLV glycol isomers before proceeding further in thesynthesis, although that separation can be accomplished by silica gelchromatography.

It is preferred that glycols XXXVIII and XLV of Charts D and E,respectively, be free of phenolic hydroxyl substituents before thealkanesulfonation step. If any of the intermediate formula-XXXVIII orformula-XLV compounds have phenolic hydroxyls, these hydroxyls arereadily converted to tetrahydropyranyloxy (OTHP) by reaction withdihydropyran, e.g. in the presence of a catalytic amount of POCl₃. The--OTHP group is subsequently replaced by OH under mildly acidicconditions.

Referring again to Charts D and E, bis(alkanesulfonic acid) esters XXXIXand XLVI are prepared by reacting glycols XXXVIII and XLV, respectively,with an alkanesulfonyl chloride or bromide, or with an alkanesulfonicacid anhydride, the alkyl in each containing one to 5 carbon atoms,inclusive. Alkanesulfonyl chlorides are preferred for this reaction. Thereaction is carried out in the presence of a base to neutralize thebyproduct acid. Especially suitable bases are tertiary amines, e.g.,dimethylaniline or pyridine. It is usually sufficient merely to mix thetwo reactants and the base, and maintain the mixture in the range 0° to25°C. for several hours. The formula-XXXIX and XLVI bis(sulfonic acid)esters are then isolated by procedures known to the art.

Referring now to Chart D, bis(sulfonic acid) esters XXXIX aretransformed either to oxa-phenylene PGE-type compounds XL, or tooxa-phenylene PGA-type compounds XLI. Referring to Chart E, bis(sulfonicacid) esters XLVI are transformed either to oxa-phenylene PGE-typecompounds XLVII, or to oxa-phenylene PGA-type compounds XLVIII.

The transformations of XXXIX and XLVI to the PGE-type compounds XL andXLVII, respectively, are carried out by reacting bis-esters XXXIX andXLVI with water in the range about 0° to about 60°C. In making theoxa-phenylene PGE₁ compounds, 25° C. is a suitable reaction temperature,the reaction then proceeding to completion in about 5 to 20 hours. It isadvantageous to have a homogenous reaction mixture. This is accomplishedby adding sufficient of a water-soluble organic diluent which does notenter into the reaction. Acetone is a suitable diluent. The desiredproduct is isolated by evaporation of excess water and diluent if one isused. The residue contains a mixture of formula-XL or formula-XLVII C-15epimers which differ in the configuration of the side chain hydroxy,that being either "natural" or "epi," i.e. α or β. These are separatedfrom by-products and from each other by silica gel chromatography. Ausual by-product is the mono-sulfonic acid ester of formula XLII (ChartD) or formula XLIX (Chart E). These mono-sulfonic acid esters areesterified to the formula-XXXIX or -XLVI bis(sulfonic acid) esters,respectively, in the same manner described above for the transformationof glycol XXXVIII or XLV to bis-ester XXXIX or XLVI and thus arerecycled back to additional formula-XL or -XLVII final product.

The transformations of XXXIX and XLVI to the PGA type compounds XLI andXLVIII, respectively, are carried out by heating bis-esters XXXIX andXLVI in the range 40° to 100° C. with a combination of water, a basecharacterized by its water solution having a pH 8 to 12, and sufficientinert water-soluble organic diluent to form a basic and substantiallyhomogenous reaction mixture. A reaction time of one to 10 hours isusually used. Preferred bases are the water-soluble salts of carbonicacid, especially alkali metal bicarbonates, e.g., sodium bicarbonate. Asuitable diluent is acetone. The products are isolated and separated asdescribed above for the transformation of bis-esters XXXIX and XLVI toPGE-type products XL and XLVII. The same mono-sulfonic acid esters XLIIand XLIX observed as by-products in those transformations are alsoobserved during preparation of PGA-type products XLI and XLVIII.

For the transformations of bis(sulfonic acid) esters XXXIX and XLVI tofinal products XL, XLI, XLVII, and XLVIII, it is preferred to use thebis-mesyl esters, i.e., compounds XXXIX and XLVI wherein R₁₃ is methyl.

Referring again to Charts D and E, the configuration of the ##EQU34##moiety in the formula-XXXIX bis-esters or the configuration of the##EQU35## moiety in the formula-XLVI bis-esters does not change duringthese transformations of XXXIX to XL, XLI, and XLII and of XLVI toXLVII, XLVIII, and XLIX. Therefore, when in formula XXXIX for example,J' is ##SPC76##

G' is --(CH₂)₄ --CH₃, and R₂, R₉ and R₂₆ are hydrogen, natural- andepi-configuration 3-oxa-4,5-inter-o-phenylene-PGE₁ esters (XL) areobtained when ##EQU36## is attached initially (XXXIX) in alphaconfiguration, and natural- and epi-configuration8-iso-3-oxa-4,5-inter-o-phenylene-PGE₁ esters (XL) are obtained whenthat moiety is attached in beta configuration. Similarly, when informula XXXIX, J' is ##SPC77##

is --(CH₂)₄ --CH₃, and R₂, R₉, and R₂₆ are hydrogen, natural- andepi-configuration 5,6-dehydro-3-oxa-4,5-inter-p-phenylene-PGE₂ estersare obtained when ##EQU37## is attached initially in alphaconfiguration, and the corresponding 8-iso compounds are obtained whenthat moiety is attached in beta configuration. The same retention of##EQU38## configuration occurs when formula-XLI and XLII compounds areproduced, and a similar retention bis-esters. ##EQU39## configurationoccurs when formula-XLVII, XLVIII, and XLIX compounds are produced fromformula-XLVI bis-esters

The PGE₃ -type oxa-phenylene compounds encompassed by formula XXXII areprepared by the transformations shown in Chart F, wherein C_(n) H_(2n),M', Q, R₂, R₅, R₉ R₁₀ R₁₃, THP, and ˜ are as defined above. ##SPC78##

Starting material, previously discussed, is converted to theformula-LXIX compound by several steps known in the art, employing firsta Wittig reaction of a phosphonium salt of a haloalkyne of the formulaBR--CHR₂ --C_(n) H_(2n) --C.tbd.C--R₅ wherein C_(n) H_(2n), R₂, and R₅are as defined above. See, for example, U. Axen et al., Chem. Comm.1969, 303, and ibid. 1970, 602.

Compound LXIX is then alkylated with an alkylation agent of the formulaHal--CH₂ --C.tbd.C--M'--COOR₁₀ wherein M', R₁₀, and Hal are as definedabove, i.e. M' is ##SPC79##

wherein C_(j) H_(2j), C_(p) H_(2p), and C_(q) H_(2q) are as definedabove,R₁₀ is the same as the definition of R₁ except that R₁₀ does notinclude hydrogen, and Hal is chloro, bromo, or iodo. These alkylatingagents have been discussed above in connection with Charts D and E andthe procedures for alkylation are similar to those employed in preparingthe acetylenic compounds above. See also Axen et al., references cited.

Accordingly, for the preparation of3-oxa-3,5-inter-m-phenylene-4-nor-PGE₃ compounds of formula XXXIIwherein C_(j) H_(2j) and C_(p) H_(2p) are valence bonds, there is usedan alkylating agent of the formula ##SPC80##

prepare, for example, from compound LX as discussed above.

Referring again to Chart F, after alkylation, compound LXX ishydroxylated to glycol LXXI. Hydroxylation reagents and procedures forthis purpose are known in the art. See also Axen et al., referencescited.

Bis(alkanesulfonic acid) esters LXXII are prepared by reacting glycolLXXI with an alkanesulfonyl chloride or bromide, for examplemethanesulfonyl chloride in the presence of a tertiary amine, by methodsknown in the art.

Referring again to Chart F, bis(sulfonic acid) esters LXXII aretransformed to oxa-phenylene bisdehydro PGE₃ -type compounds LXXIII byreaction with water in the range about 0° to about 60° C., preferably inan acetone-water mixture, as known in the art and discussed hereinabove.See also Axen, references cited.

Transformation of LXXIII to the PGE₃ -type compounds LXXIV isaccomplished by hydrogenation of LXXIII using a catalyst which catalyzeshydrogenation of --C.tbd.C-- only to cis--CH=CH--, as known in the artand discussed hereinabove. Preferred is Lindlar catalyst in the presenceof quinoline, see Axen, references cited.

The product is a mixture of formula-LXXIV C-15 epimers which areseparated from by-products and from each other by silica gelchromatography.

The transformations of the formula-LXXIV PGE₃ -type products to thecorresponding PGF₃, PGA₃, and PGB₃ products are carried out by the stepsshown in Chart A, discussed hereinabove.

The formula-LX and XLVII oxa-phenylene PGE-type compounds and theformula-XLI and XLVIII oxa-phenylene PGA-type compounds shown in ChartsD and E and the formula-LXXIV oxa-phenylene PGE₃ -type compounds shownin Chart F are all R₁₀ carboxylic acid esters, wherein R₁₀ is as definedabove. Moreover when those PGE-type and PGA-type R₁₀ esters are used toprepare the other oxa-phenylene prostaglandin-like compounds accordingto Charts A, B, and C, corresponding R₁₀ esters are likely to beproduced, especially in the case of the oxa-phenylene PGF-typecompounds. For some of the uses described above, it is preferred thatthe novel formula XVI-to-XXXV oxa-phenylene prostaglandin-like compoundsof this invention be in free acid form, or in salt form which requiresthe free acid as a starting material. Likewise, when a formulaXVI-to-XXXV oxa-phenylene prostaglandin-like compound is available as anester, say the methyl ester, and another ester is desired, it is usuallynecessary to convert the available ester to the free acid form and fromit prepare the desired ester. Esters are prepared by methods known inthe art or described herein, for example by reaction withdiazohydrocarbons.

The PGF-type esters of formulas XX-XXIII and XXXIII and the PGB-typecompounds of formulas XXVIII-XXXI and XXXV are easily hydrolyzed orsaponified to the free acids by the usual known procedures, especiallywhen R₁ (R₁₀) is alkyl of one to 4 carbons, inclusive, preferably methylor ethyl.

On the other hand, the PGE type esters of formulas XVI-XIX and XXXII andthe PGA type esters of formulas XXIV-XXVII and XXXIV are difficult tohydrolyze or saponify without causing unwanted structural changes in thedesired acids. There are two other procedures to make the free acidforms of these PGE- and PGA-type compounds.

One of those procedures is applicable mainly in preparing the free acidsby subjecting their alkyl esters to the acylase enzyme system of amicroorganism species of Subphylum 2 of Phylum III, and thereafterisolating the acid. See West Germany Offenlegungsschrift No. 1,937,678;Derwent Farmdoc No. 6863R. This enzymatic hydrolysis is also applicableto the above PGF- and PGB-type alkyl esters. Another method using anesterase enzyme composition from P. homomalla is described in U.S. Pat.No. 3,761,356.

Another procedure for making the free acids of the above PGE- andPGA-type compounds involves treatment of certain haloethyl esters ofthose acids with zinc metal and an alkanoic acid of 2 to 6 carbon atoms,preferably acetic acid. Those haloethyl esters are the esters whereinR₁₀ is ethyl substituted in the β-position with 3 chloro, 2 or 3 bromo,or one, 2, or 3 iodo. Of those haloethyl moieties, β,β,β-trichloroethylis preferred. Zinc dust is preferred as the physical form of the zinc.Mixing the haloethyl ester with the zinc dust at about 25° C. forseveral hours usually causes substantially complete replacement of thehaloethyl moiety of the formula XVI-XIX, XXXII, XXIV-XXVII, and XXXIVester with hydrogen. The free acid is then isolated from the reactionmixture by procedures known to the art. This procedure is alsoapplicable to the production of PGF- and PGB-type free acids.

Formula-XXXVII cyclic ketals and formula XLIV olefins wherein R₁₀ ishaloethyl as above defined are necessary as intermediates for this routeto the final PGE, PGF, PGA, and PGB type free acids. Theseformula-XXXVII and -XLIV haloethyl ester intermediates can be preparedby alkylation of cyclic ketal XXXVI (Chart D) or olefin XLIII (Chart E),respectively, with the appropriate formula LIII-to-LVI or LXVII-LXVIIIalkylating agent wherein R₁₀ is haloethyl as above defined. However,preferred routes of the formula-XXXVII and -XLIV haloethyl esterintermediates are shown in Charts G and H.

In Charts G and H, G, J', R₂, R₉, R₂₆, R₁₁, R₁₂, Z', and ˜ are asdefined above. Haloethyl represents ethyl substituted in the β-positionwith 3 chloro, or 2 or 3 bromo, or 1, 2, or 3 iodo, preferably --CH₂CCl₃. R₁₅ represents alkyl of one to 4 carbon atoms, inclusive,preferably methyl or ethyl. ##SPC81## ##SPC82##

Compound LXXVI in Chart G is within the scope of compound XXXVII inChart D. Compound LXXXII in Chart H is within the scope of compound XLIVin Chart E. These ketones LXXVI and LXXXII are reduced to correspondinghydroxy compounds LXXVII and LXXXIII, respectively, with a carbonylreducing agent, e.g., sodium borohydride, as described above indiscussion of Chart A. Then, hydroxy esters LXXVII and LXXXIII aresaponified by known procedures to hydroxy acids LXXVIII and LXXXIV,respectively. These two hydroxy acids are transformed to keto haloethylesters LXXXI and LXXXVI, respectively, by oxidation of the hydroxy groupto keto and esterification of the carboxyl group to --COO-haloethyl. Asshown in Charts G and H, these two reactions are carried out in eitherorder. However, it is preferred to oxidize first and then esterify.

Hydroxy acids LXXVIII and LXXXIV are oxidized to keto acids LXXX andLXXXVI, respectively, and hydroxy haloesters LXXIX and LXXXV areoxidized to keto haloesters LXXXI and LXXXVII, respectively, by reactionwith an oxidizing agent which does not attack other parts of thesemolecules, especially the cyclic ketal group of compounds LXXVIII andLXXIX or ethylenic linkage of compounds LXXIV and LXXXV. An especiallyuseful reagent for this purpose is the Jones reagent, i.e., acidicchromic acid. Acetone is a suitable diluent for this purpose, and aslight excess of oxidant and temperatures at least as low as about 0°C., preferably about -10° to about -20° C. should be used. The oxidationproceeds rapidly and is usually complete in about 5 to about 30 minutes.Excess oxidant is destroyed, for example, by addition of a loweralkanol, advantageously isopropyl alcohol, and the aldehyde is isolatedby conventional methods, for example, by extraction with a suitablesolvent, e.g., diethyl ether. Other oxidizing agents can also be used.Examples are mixtures of chromium trioxide and pyridine or mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide. See, for example, J.Am. Chem. Soc. 87, 5661 (1965).

Haloethyl esters LXXIX, LXXXI, LXXXV, and LXXXVII are prepared byreacting agents LXXVIII, LXXX, LXXXIV, and LXXXVI respectively, with theappropriate haloethanol, e.g., β,β,β-trichloroethanol, in the presenceof a carbodiimide, e.g., dicyclohexylcarbodiimide, and a base, e.g.,pyridine, preferably in the presence of an inert liquid diluent, e.g.,dichloromethane, for several hours at about 25° C.

As described above, the alkylations of cyclic ketal XXXVI to XXXVII(Chart D) and olefin XLIII and XLIV (Chart E) usually produce mixturesof alpha and beta alkylation products with respect to the ##EQU40##moities. Also as described above, those two isomers lead to differentfinal products, alpha leading to the PG-type series and beta leading tothe 8-iso-PG-type series. If a compound in one or the other of those twoseries is preferred, there are two methods for favoring production ofthe preferred final product.

One of those methods involves isomerization of the final product offormulas XVI to XXXV. Either the alpha isomer of a formula XVI-to-XXXVcompound, ester or free acid, or the corresponding beta isomer ismaintained in a inert liquid diluent in the range 0° to 80° C. and inthe presence of a base characterized by its water solution having a pHbelow about 10 until a substantial amount of the isomer has beenisomerized to the other isomer, i.e., alpha to beta or beta to alpha.Preferred bases for this purpose are the alkali metal salts ofcarboxylic acids, especially alkanoic acids of 2 to 4 carbon atoms,e.g., sodium acetate. Examples of useful inert liquid diluents arealkanols of one to 4 carbon atoms, e.g., ethanol. This reaction at about25° takes about one to about 20 days. Apparently an equilibrium isestablished. The mixtures of the two isomers, alpha and beta, areseparated from the reaction mixture by known procedures, and then thetwo isomers are separated from each other by known procedures, forexample, chromatography, recrystallization, or a combination of those.The less preferred isomer is then subjected to the same isomerization toproduce more of the preferred isomer. In this manner by repeatedisomerizations and separations, substantially all of the less preferredisomer of the formula XVI-to-XXXV compound is transformed to morepreferred isomer.

The second method for favoring production of a preferred formulaXVI-to-XXXV isomer involves any one of the keto intermediates offormulas XXXVII, XXXVIII, XLIV, XLV, LXX, or LXXI (Charts D, E, and F).Either the alpha form or the beta form of one of those intermediates istransformed to a mixture of both isomers by maintaining one or the otherisomer, alpha or beta, in an inert liquid diluent in the presence of abase and in range 0°to 100° C. until a substantial amount of thestarting isomer has been isomerized to the other isomer. Preferred basesfor this isomerization are alkali metal amides, alkalie metal alkoxides,alkali metal hydrides, and triarylmethyl alkali metals. Especiallypreferred are alkali metal tert-alkoxides of 4 to 8 carbon atoms, e.g.,potassium tert-butoxide. This reaction at about 25° C. proceeds rapidly(one minute to several hours). Apparently an equilibrium mixture of bothisomers is formed, starting with either isomer. The isomer mixtures inthe equilibrium mixture thus obtained are isolated by known procedures,and then the two isomers are separated from each other by knownprocedures, for example, chromatography. The less preferred isomer isthen subjected to the same isomerization to produce more of thepreferred isomer. In this manner, by repeated isomerizations andseparations, substantially all of the less preferred isomer of any ofthese intermediates in transformed to the more preferred isomer. Cyclicketalketone intermediates of formula XXXVII are preferred over the otherintermediates for this isomerization procedure.

The novel oxa-phenylene PGE, PGF, PGA and PGB type compounds of formulaXVI to XXXV wherein R₂ is alkyl of one to 4 carbon atoms, inclusive,preferably methyl or ehtyl, are preferred over the correspondingoxa-phenylene PGE, PGF, PGA, and PGB type compounds in which R₂ ishydrogen for the above-described pharmacological purposes.

These 15-alkyl prostaglandin analogs are suprisingly and unexpectedlymore useful than the corresponding 15-hydrogen compounds for the reasonthat they are substantially more specific with regard to potency incausing prostaglandin-like biological responses, and have substantiallylonger duration of biological activity. For that reason, fewer andsmaller doses of these 15-alkyl prostaglandin analogs are needed toattain the desired pharmacological results.

Although the above-mentioned 15-alkyl compounds are produced by themethods outlined above in Charts A-F, the preferred methods are setforth in Chart I and J as follows.

In Chart I is shown the transformation of 15-alkyl PGF-type acids andalkyl esters to the corresponding PGE-type acids and alkyl esters byoxidation. For this purpose, and oxidizing agent is used whichselectively oxidizes secondary hydroxy groups to carbonyl groups in thepresence of carbon-carbon double bonds. Formula LXXXVIII in Chart Iincludes optically active compounds as shown and racemic compounds ofthat formula and the mirror images thereof, and also the 15-epimers ofboth of those, i.e., wherein the configuration at C-15 is β rather thanα as shown. Also in Chart I, E', G, J', R₁ and R₂₆ are as defined above,and R₁₆ is alkyl of one to 4 carbon atoms.

For the transformations of Chart I, the β-hydroxy isomers of reactantLXXXVIII are preferred starting materials when the carboxyl side chainis alpha, although the corresponding α-hydroxy isomers are also usefulfor this purpose.

Oxidation reagents useful for the transformation set forth in Chart Iare known to the art. An especially useful reagent for this purpose isthe Jones reagent, i.e., acidified chromic acid. See J. Chem. Soc. 39(1946). A slight excess beyond the amount necessary to oxidize one ofthe secondary hydroxy groups of the formula-LXXXVIII reactant is used.Acetone is a suitable diluent for this purpose. Reaction temperatures atleast as low as about 0° C. should be used. ##SPC83##

Preferred reaction temperatures are in the range -10° to -50° C. Theoxidation proceeds rapidly and is usually complete in about 5 to 20minutes. The excess oxidant is destroyed, for example by addition of alower alkanol, advantageously, isopropyl alcohol, and the formula-LXXXIXPGE-type product is isolated by conventional methods.

Examples of other oxidation reagents useful for the Chart Htransformations are silver carbonate on Celite (Chem. Commun. 1102(1969)), mixtures of chromium trioxide and pyridine (Tetrahedron Letters3363 (1968), J. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351(1962)), mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide(J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87,5661 (1965)).

The novel 15-alkyl oxa-phenylene PGF.sub.α- and PGF.sub.β-type acids andesters of formulas XX-XXIIII and XXXIII wherein R₂ is one to 4 carbonatoms, inclusive, are preferably prepared from the corresponding15-hydrogen compounds by the sequence of transformations shown in ChartJ, wherein formulas XC through XCIV, inclusive, include optically activeand racemic natural- and epi-configuration compounds of those formulasand the mirror images thereof. Also in Chart J, R₁₆ is alkyl of one to 4carbon atoms, inclusive, and E', G, Hal, J', R₁, R₂₆, and ˜ are asheretofore defined; G" in formula XCII is the same as G except that T isreplaced by T", wherein T" is the same as T above except that, in R₆,--Si(R₈)₃ replaces hydrogen. Also in Chart J, R₈ is alkyl of one to 4carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive,phenyl, or phenyl substituted with one or 2 fluoro, chloro, or alkyl ofone to 4 carbon atoms inclusive, and R₁₇ is R₁ as defined above or silylof the formula-Si--(R₈)₃ wherein R₈ is as defined above. The various R₈'s of a --Si(R₈)₃ moiety are alike or different. For example, a--Si(R₈)₃ can be trimethylsilyl, dimethylphenylsilyl, ormethylphenylbenzylsilyl. Examples of alkyl of one to 4 carbon atoms,inclusive, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, and tert-butyl. Examples of aralkyl of 7 to 12 carbon atoms,inclusive, are benzyl, phenethyl, α-phenylethyl, 3-phenylpropyl,α-naphthylmethyl, and 2-(β-naphthyl)ethyl. Examples of phenylsubstituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbonatoms, inclusive, are p-chlorophenyl, m-fluorophenyl, o-tolyl,2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, and2,4-dichloro-3- methylphenyl.

In Chart J, the final PGF.sub.α and PGF.sub.β-type products are thoseencompassed by formulas XCIII and XCIV, respectively.

The initial optically active or racemic reactants of formula XC in ChartJ i.e., the oxa-phenylene PGF₁ -, PGF₂ -, 5,6-dehydro-PGF₂ -, anddihydro-PGF₁ -type compounds in their α and β forms, and their esters,are prepared by methods described herein. Thus, racemic oxa-phenylenedihydro-PGF₁ .sub.α- and -PGF₁ .sub.β-type compounds, and their estersare prepared by catalytic hydrogenation of the corresponding racemicoxa-phenylene PGF₁ .sub.α or PGF₂ .sub.β, and PGF₁ .sub.β or PGF₂.sub.βtype compounds, respectively, e.g. in the presence of 5%palladium-on-charcoal catalyst in ethyl acetate solution at 25° C. andone atmosphere pressure of hydrogen.

The heretofore-described acids and esters of formula XC are transformedto the corresponding intermediate 15-dehydro acids and esters of formulaXCI, by oxidation with reagents such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone, activated manganese dioxide,or nickel peroxide (see Fieser et al., "Reagents for Organic Syntheses,"John Wiley & Sons, Inc., New York, N.Y. pp. 215, 637, and 731).Alternatively, and especially for the formula-XC reactants wherein E' is--CH₂ CH₂ and J' is L as defined above, these oxidations are carried outby oxygenation in the presence of the 15-hydroxyprostaglandindehydrogenase of swine lung (see Arkiv for Kemi 25, 293 (1966)). Thesereagents are used according to procedures known in the art. See, forexample, J. Biol. Chem. 239, 4097 (1964).

Referring again to Chart J, intermediate compounds of formula XCI aretransformed to silyl derivatives of formula XCII by procedures known inthe art. See, for example, Pierce, "Silylation of Organic Compounds,"Pierce Chemical Co., Rockford, Ill. (1968). Both hyroxy groups of theformula-XCI reactants are thereby transformed to --O--Si(R₈)₃ moietieswherein R₈ is as defined above, and sufficient of the silylating agentis used for that purpose according to known procedures. When R₁ in theformula-XCI intermediate is hydrogen, the --COOH moiety thereby definedis simultaneously transformed to --COO--Si(R₈)₃, additional silylatingagent being used for this purpose. This latter transformation is aidedby excess silylating agent and prolonged treatment. Likewise, when R₆ inT of the formula-XCI intermediate is hydrogen, the phenolic hydroxylthereby defined is simultaneously transformed to --O--Si(R₈)₃ in thesilylation step. G" in formula XCII, as defined above, therefore is thesame as G except that T is replaced by T", wherein T" is the same as Tabove except that, in R₆, --Si(R₈)₃ replaces hydrogen. When R₁ informula XCI is alkyl, then R₁₇ in formula XCII will also be alkyl. Thenecessary silylating agents for these transformations are known in theart or are prepared by methods known in the art. See, for example, Post,"Silicones and Other Organic Silicon Compounds," Reinhold PublishingCorp., New York, N.Y. (1949).

Referring again to Chart J, the intermediate silyl compounds of formulaXCII are transformed to the final compounds of formulas XCIII and XCIVby first reacting the silyl compound with a Grignard reagent of theformula R₁₆ MgHal wherein R₁₆ is as defined above, and Hal is chloro,bromo, or iodo. For this purpose, it is preferred that Hal be bromo.This reaction is carried out by the usual procedure for Grignardreactions, using diethyl ether as a reaction solvent and saturatedaqueous ammonium chloride solution to hydrolyze the Grignard complex.The resulting disilyl, trisilyl, or tetrasilyl tertiary alcohol is thenhydrolyzed with water to remove the silyl groups. For this purpose, itis advantageous to use a mixture of water and sufficient of awater-miscible solvent, e.g., ethanol to give a homogenous reactionmixture. The hydrolysis is usually complete in 2 to 6 hours at 25° C.,and is preferably carried out in an atmosphere of an inert gas, e.g.,nitrogen or argon.

The mixture of 15-α and 15-β isomers obtained by this Grignard reactionand hydrolysis is separated by procedures known in the art forseparating mixtures of prostanoic acid derivatives, for example, bychromatography on neutral silica gel. In some instances, the lower alkylesters, especially the methyl esters of a pair of 15-α and 15-β isomersare more readily separated by silica gel chromatography than are thecorresponding acids. In those cases, it is advantageous to esterify themixture of acids as described below, separate the two esters, and then,if desired, saponify the esters by procedures known in the art forsaponification of prostaglandins F.

Although formula-XCIII and -XCIV compounds wherein E' is --CH₂ CHR₉--and J' is L' as defined above may be produced according to theprocesses of Chart J, it is preferred to produce those noveldihydro-PGF₁ analogs by hydrogenation of one of the correspondingunsaturated compounds, i.e., a compound of formula XCIII or XCIV whereinE is trans --CH=CR₉ --and J' is either L', --CH=CH--M'--,--C.tbd.C--M'-, M' being defined above. This hydrogenation isadvantageously carried out catalytically, for example, in the presenceof a 5% palladium-on-charcoal catalyst in ethyl acetate solution at 25°C. and one atmosphere pressure of hydrogen.

The novel 15-alkyl oxa-phenylene PGA-type and PGB-type acids and estersof formula XXIV-XXXI and XXXIV-XXXV are prepared from the 15-alkyloxa-phenylene PGE compounds, heretofore described, by dehydrations anddouble bond migrations previously described, as shown in Chart A.Likewise the 15-alkyl PGB-type compounds are prepared by contacting the15-alkyl PGA-type compounds with base. For the transformation of the15-alkyl PGE-type compounds to the 15-alkyl PGA-type compounds of thisinvention (Chart K), it is preferred that a dehydrating agent be usedwhich removes ##SPC84##

the hydroxy group from the alicyclic ring in the presence of a hydroxygroup on a tertiary carbon atom. In Chart K, E', G, J', R₁, R₂, R₂₆, and˜ are as defined above. Formula XCV as shown includes optically activecompounds and racemic compounds of that formula and the mirror imagesthereof, and also the 15-epimers of both of those. Any of the knownsubstantially neutral dehydrating agents is used for these reactions.See Fieser et al., cited above. Preferred dehydrating agents aremixtures of at least an equivalent amount of a carbodiimide and acatalytic amount of a copper (II) salt. Especially preferred aremixtures of at least an equivalent amount of dicyclohexyl carbodiimideand a catalytic amount of copper (II) chloride. An equivalent amount ofa carbodiimide means one mole of the carbodiimide for each mole of theformula-XCV reactant. To ensure completeness of the reaction, it isadvantageous to use an excess of carbodiimide, i.e., 1.5 to 5 or evenmore equivalents of the carbodiimide.

The dehydration is advantageously carried out in the presence of aninert organic diluent which gives a homogeneous reaction mixture withrespect to the formula-XCV reactant and the carbodiimide. Diethyl etheris a suitable diluent. It is advantageous to carry out the dehydrationin an atmosphere of an inert gas, e.g., nitrogen, helium, or argon. Thetime required for the dehydration will depend in part on the reactiontemperature. With the reaction temperature in the range 20° to 30°C.,the dehydration usually takes place in about 40 to 60 hours. Theformula-XCVI product is isolated by methods known in the art, e.g.,filtration of the reaction mixture and evaporation of the filtrate. Theproduct is then purified by methods known in the art, advantageously bychromatography on silica gel.

The final formula XVI-to-XXXV compounds prepared by the processes ofthis invention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed above. These transformations are carriedout by a variety of procedures known in the art to be generally usefulfor the preparation of inorganic, i.e., metal or ammonium, salts, amineacid addition salts, and quaternary ammonium salts. The choice ofprocedure depends in part upon the solubility characteristics of theparticular salt to be prepared. In the case of the inorganic salts, itis usually suitable to dissolve the formula XVI-to-XXXV acid in watercontaining the stoichiometric amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. For example,such use of sodium hydroxide, sodium carbonate, or sodium bicarbonategives a solution of the sodium salt. Evaporation of the water oraddition of a water-miscible solvent of moderate polarity, for example,a lower alkanol or a lower alkanone, gives the solid inorganic salt ifthat form is desired.

To produce an amine salt, the formula XVI-to-XXXV acid is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the latterare diethyl ether and benzene. At least a stoichiometric amount of theamine corresponding to the desired cation is then added to thatsolution. If the resulting salt does not precipitate, it is usuallyobtained in solid form by addition of a miscible diluent of low polarityor by evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use stoichiometricamounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe formula XVI-to-XXXV acid with the stoichiometric amount of thecorresponding quaternary ammonium hydroxide in water solution, followedby evaporation of the water.

The final formula XVI-to-XXXV acids or esters prepared by the processesof this invention are transformed to lower alkanoates by interaction ofthe formula XVI-to-XXXV hydroxy compound with a carboxyacylating agent,preferably the anhydride of a lower alkanoic acid, i.e., an alkanoicacid of one to 8 carbon atoms, inclusive. For example, use of aceticanhydride gives the corresponding diacetate. Similar use of propionicanhydride, isobutyric anhydride, and hexanoic acid anhydride gives thecorresponding carboxyacylates.

The carboxyacylation is advantageously carried out by mixing the hydroxycompound and the acid anhydride, preferably in the presence of atertiary amine such as pyridine or triethylamine. A substantial excessof the anhydride is used, preferably about 10 to about 10,000 moles ofanhydride per mole of the hydroxy compound reactant. The excessanhydride serves as a reaction diluent and solvent. An inert inorganicdiluent, for example, dioxane, can also be added. It is preferred to useenough of the tertiary amine to neutralize the carboxylic acid producedby the reaction, as well as any free carboxyl groups present in thehydroxy compound reactant.

The carboxyacylation reaction is preferably carried out in the rangeabout 0° to about 100° C. The necessary reaction time will depend onsuch factors as the reaction temperature, and the nature of theanhydride and tertiary amine reactants. With acetic anhydride, pyridine,and a 25° C. reaction temperature, a 12 to 24-hour reaction time isused.

The carboxyacylated product is isolated from the reaction mixture byconventional methods. For example, the excess anhydride is decomposedwith water, and the resulting mixture acidified and then extracted witha solvent such as diethyl ether. The desired carboxyacylate is recoveredfrom the diethyl ether extract by evaporation. The carboxyacylate isthen purified by conventional methods, advantageously by chromatography.

By this procedure, the formula XVI-XIX and XXXII PGE-type compounds aretransformed to dialkanoates, the formula XX-XXIII and XXXIII PGF-typecompounds are transformed to trialkanoates, and the formula XXIV-XXXIand XXXIV-XXXV PGA-type and PGB-type compounds are transformed tomonoalkanoates.

When a PGE-type dialkanoate is transformed to a PGF-type compound bycarbonyl reduction as shown in Chart A, a PGF-type dialkanoate is formedand is used for the above-described purposes as such or is transformedto a trialkanoate by the above-described procedure. In the latter case,the third alkanoyloxy group can be the same as or different from the twoalkanoyloxy groups present before the carbonyl reduction.

Molecules of each of the compounds encompassed by formulas XVI to XXXVand, except for XLIII and L, of each intermediate formula each have atleast one center of asymmetry, and each can exist in racemic form and ineither enantiomeric form, i.e., d and l. A formula accurately definingthe d form would be the mirror image of the formula which defined the lform. Both formulas are necessary to define accurately the correspondingracemic form. The various formulas XVI-to-XXXV as drawn each representsthe optically active form with the same configuration as thenaturally-occurring prostaglandins.

When an optically active (d or l) final compound is desired, that ismade by resolution of the racemic compound or by resolution of one ofthe asymmetric racemic intermediates. These resolutions are carried outby procedures known in the art. For example, when final compound XVI toXXXV is a free acid, the dl form thereof is resolved into the d and lforms by reacting said free acid by known general procedures with anoptically active base, e.g., brucine or strychnine, to give a mixture oftwo diastereoisomers which are separated by known general procedures,e.g., fractional crystallization, to give the separate diastereiosomericsalts. The optically active acid of formula XVI to XXXV is then obtainedby treatment of the salt with an acid by known general procedures.Alternatively, the free acid form of cyclic ketal XXXVII, olefins XLIVor LXX, or glycols XXXVIII, XLV, or LXXI is resolved into separate d andl forms and then esterified and transformed further to the correspondingoptically active form of the final product XVI to XXXV as describedabove.

In another method, bicyclo ketone reactants XXXVIII, XLV, or LXXI in exoor endo form, are transformed to ketals with an optically active1,2-glycol, e.g., D-(--)-2,3-butanediol, by reaction of said 1,2-glycolwith the formula-XXXVIII, XLV, or LXXI compound in the presence of astrong acid, e.g., p-toluenesulfonic acid. The resulting ketal is amixture of diastereoisomers which is separated into the d and ldiastereoisomers, each of which is then hydrolyzed with an acid, e.g.,oxalic acid, to the original keto compound, now in optically activeform. These reactions involving optically active glycols and ketals forresolution purposes are generally known in the art. See, for example,Chem. Ind. 1664 (1961) and J. Am. Chem. Soc. 84, 2938 (1962). Dithiolsmay be used instead of glycols.

Still another procedure for obtaining optically active oxa-phenylenePGF-type compounds is by stereoselective microbiological reduction ofthe racemic oxa-phenylene PGE compounds. For this purpose activelyfermenting baker's yeast is employed. The PGE compound is contacted witha yeast-sugar-water mixture at about 25° C. for 24-48 hours. There isproduced by reduction a mixture of the PGF.sub.α compound and theenantiomeric PGF.sub.β compound, which are separable by silica gelchromatography for example. Accompanying this transformation, carboxylicester groups are removed by hydrolysis. Accordingly, fromdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ methyl ester, there areobtained natural configuration3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub.α and enantiomeric3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub.β.

An alternate method of synthesis is provided hereinafter for a group ofoxa-phenylene analogs within the scope of formulas XVI and XX above,represented by the following formulas XCVII-CIV; ##SPC85##

and the racemic mixtures of those compounds and their respectiveenantiomers represented by the mirror images of the above formulas. Theterms C_(p) H_(2p), C_(t) H_(2t), R₁, R₂, T, and s are as defined above;R₃₀ is alkyl of 2 to 10 carbon atoms, inclusive, substituted with zero,one, 2, or 3 fluoro.

The alternate method of synthesis disclosed hereinafter is also usefulfor preparing oxa-phenylene 17,18-didehydro prostaglandin analogs withinthe scope of formulas CV-CVIII: ##SPC86##

wherein C_(n) H_(2n), C_(p) H_(2p), R₁, R₂, and R₅ are as defined andused above.

These 17,18-didehydro analogs of formulas CV-CVIII together withcompounds of formulas XXXII and XXXIII above are within the scope of17,18-didehydro PGE- and PGF-type compounds represented by the formulas:##SPC87##

wherein ˜ indicates attachment of the hydroxyl or the side chain to thecyclopentane ring in alpha or beta configuration; wherein V is (1) C_(g)H_(2g) or (2) --CH=CH-- C_(j) H_(2j) --, wherein C_(g) H_(2g) representsa valence bond or alkylene of one to 4 carbon atoms, inclusive, with oneor 2 chain carbon atoms between --CH₂ -- and the phenylene ring, andwherein C_(j) H_(2j) represents a valence bond or alkylene of one or 2carbon atoms with one chain carbon atom between --CH=CH-- and thephenylene ring; wherein C_(n) H_(2n) is alkylene of one to 4 carbonatoms, inclusive; wherein C_(p) H_(2p) represents a valence bond oralkylene of one to 4 carbon atoms, inclusive, with one or 2 chain carbonatoms between the ring and --O--; wherein C_(g) H_(2g) and C_(p) H_(2p)together represent zero to 8 carbon atoms, inclusive, with total chainlengths zero to 3 carbon atoms, inclusive; wherein Q is ##EQU41##wherein R₂ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro oralkyl of one to 4 carbon atoms, inclusive; and wherein R₅ is alkyl ofone to 4 carbon atoms, inclusive, substituted with zero, one, 2, or 3fluoro.

The corresponding 17,18-didehydro PGA- and PGB-type compounds areavailable by methods disclosed herein or known in the art, for exampleby acid or base dehydration of the formula-CXXXVII PGE-type compounds.

The alternate method of synthesis utilizes oxetane intermediates havingthe grouping ##SPC88##

prepared from bicyclo hexene starting materials.

Reference to Chart L will make clear the steps by which startingmaterial CIX is transformed to product CXVIII. The formula-CIX compoundwherein R₃₁ and R₃₂ together are --CH₂ --C(CH₃)₂ --CH₂ -- and ˜ is endo,i.e. bicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde neopentyl glycolacetal, is available either in racemic or optically active form. SeeU.S. Pat. No. 3,711,515.

In Chart L the symbols used therein have the same meanings as definedabove, as to C_(p) H_(2p), G, Q, R₁, R₂, R₃₁, R₃₂, R₃₉, R₄₂, and ˜. R₄₃represents hydrogen, carboxyacyl R₃₉, benzoyl, substituted benzoyl,mono-esterified phthaloyl, and substituted naphthoyl. Furthermore, inChart L and likewise in the other charts of this specification, theformulas as drawn represent specific optical isomers following theconventions applied herein to the end products. However, for purposes ofconvenience and brevity it is intended that such representations of theprocess steps for the optically active intermediates are applicable tothose same process steps as used for the corresponding racemicintermediates.

Both the endo and exo forms of bicyclo hexene CIX are available or aremade by methods known in the art, in either their racemic or opticallyactive forms. See. U.S. Pat. No. 3,711,515. ##SPC89##

Either the endo or exo starting material will yield the ultimate analogsof formula CXVIII by the processes of Chart L.

In step (a) oxetane CX is obtained by reaction of the formula-CIXbicyclo hexene with an aldehyde of the formula ##SPC90##

wherein C_(p) H_(2p) represents a valence bond or alkylene of one to 4carbon atoms, inclusive, with one or 2 carbon atoms in the chain betweenthe phenylene ring and --O--, and wherein R₃₉ is carboxyacyl of theformula ##EQU42## wherein R₄₀ is hydrogen, alkyl of one to 19 carbonatoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive, whereinalkyl or aralkyl are substituted with zero to 3 halo atoms.

The formula-CXIX aldehydes are available or readily prepared by methodsknown in the art. Examples of such compounds within the scope of formulaCXIX are: ##SPC91##

The formation of oxetane CX is accomplished by photolysis of a mixtureof the bicyclo hexene and the aldehyde in a solvent. The bicyclo hexeneis preferably used in excess over the molar equivalent, for example 2 to4 times the theoretical equivalent amount. The solvent is aphotochemically inert organic liquid, for example liquid hydrocarbons,including benzene or hexane, 1,4-dioxane, and diethyl ether. Thereaction is conveniently done at ambient conditions, for example 25° C.,but may be done over a wide range of temperature, from about -78° C. tothe boiling point of the solvent. The irradiation is done with mercuryvapor lamps of the low or medium pressure type, for example thosepeaking at 3500 A. Such sources are available from The Southern NewEngland Ultraviolet Co., Middletown, Conn. Alternatively, those lampswhich emit a broad spectrum of wavelengths and which may be filtered totransmit only light of λ˜3000-3700 A may also be used. For a review ofphotolysis see D. R. Arnold in "Advances in Photochemistry," Vol. 6, W.A. Noyes et al., Wiley-Interscience, New York, 1968, pp. 301-423.

In step (b) the cleavage of the oxetane ring to yield the formula-CXIcompounds is accomplished with an alkali metal in the presence of aprimary amine or alcohol. Preferred is lithium in ethylamine, or sodiumin ethyl alcohol. See L. J. Altman et al., Synthesis 129 (1974). Thecleavage transformation may also be accomplished by catalytichydrogenation over an inert metal catalyst, e.g. Pd on carbon, in ethylacetate or ethanol.

In step (c) the formula CXI diol is prepared for step (d) by preferablyblocking the two hydroxyl groups with carboxyacyl groups within thescope of R₃₉, i.e. ##EQU43## as defined above. For example, the diol istreated with an acid anhydride such as acetic anhydride, or with an acylhalide in a tertiary amine. Expecially preferred is pivaloyl chloride inpyridine.

Other carboxyacylating agents useful for this transformation are knownin the art or readily obtainable by methods known in the art, andinclude carboxyacyl halides, preferably chlorides, bromides, orfluorides, i.e. R₄₀ C(O)Cl, R₄₀ C(O)Br, or R₄₀ C(O)F, and carboxyacidanhydrides, (R₄₀ C--)₂ O, wherein R₄₀ is as defined above. The preferredreagent is an acid anhydride. Examples of acid anhydrides useful forthis purpose are acetic anhydride, propionic anhydride, butyricanhydride, pentanoic anhydride, nonanoic anhydride, trideconoicanhydride, steric anhydride, (mono, di or tri) chloroacetic anhydride,3-chlorovaleric anhydride, 3-(2-bromoethyl)-4,8-dimethylnonanoicanhydride, cyclopropaneacetic anhydride, 3-cycloheptanepropionicanhydride, 13-cyclopentanetridecanoic anhydride, phenylacetic anhydride,(2 or 3)-phenylpropionic anhydride, 13-phenyltridecanoic anhydride,phenoxyacetic anhydride, benzoic anhydride, (o, m, or p)-bromobenzoicanhydride, 2,4 (or 3,4)-dichlorobenzoic anhydride,p-trifluoromethylbenzoic anhydride, 2-chloro-3-nitrobenzoic anhydride,(o, m, or p)-nitrobenzoic anhydride, (o, m, or p)-toluic anhydride,4-methyl-3-nitrobenzoic anhydride, 4-octylbenzoic anhydride, (2,3, or4)-biphenylcarboxylic anhydride, 3-chloro-4-biphenylcarboxylicanhydride, 5-isopropyl-6-nitro-3-biphenylcarboxylic anhydride, and (1 or2)-naphthoic anhydride. The choice of anhydride depends upon theidentity of R₄₀ in the final acylated product, for example when R₄₀ isto be methyl, acetic anhydride is used; when R₄₀ is to be 2-chlorobutyl,3-chlorovaleric anhydride is used.

When R₄₀ is hydrogen, ##EQU44## is formyl. Formylation is carried out byprocedures known in the art, for example, by reaction of the hydroxycompound with the mixed anhydride of acetic and formic acids or withformylimidazole. See, for example, Fieser et al., Reagents for OrganicSynthesis, John Wiley and Sons, Inc., pp. 4 and 407 (1967) andreferences cited therein. Alternatively, the formula CXI diol is reactedwith two equivalents of sodium hydride and then with excess ethylformate.

In formula CXII, R₄₃ may also represent a blocking group includingbenzoyl, substituted benzoyl, monoesterified phthaloyl and substitutednaphthoyl. For introducing those blocking groups, methods known in theart are used. Thus, an aromatic acid of the formula R₃₉ OH, wherein R₃₉is as defined above, for example benzoic acid, is reacted with theformula-CXI compound in the presence of a dehydrating agent, e.g.sulfuric acid, zinc chloride, or phosphoryl chloride; or an anhydride ofthe aromatic acid of the formula (R₃₉)₂ O, for example benzoicanhydride, is used.

Preferably, however, an acyl halide, e.g. R₃₉ Cl, for example benzoylchloride, is reacted with the formula-CXI compound in the presence of atertiary amine such as pyridine, triethylamine, and the like. Thereaction is carried out under a variety of conditions using proceduresgenerally known in the art. Generally, mild conditions are employed,e.g. 20°-60° C., contacting the reactants in a liquid medium, e.g.excess pyridine or an inert solvent such as benzene, toluene orchloroform. The acylating agent is used either in stoichiometric amountor in excess.

As examples of reagents providing R₃₉ for the purposes of thisinvention, the following are available as acids (R₃₉ OH), anhydrides((R₃₉)₂ O), or acyl chlorides (R₃₉ Cl): benzoyl; substituted benzoyl,e.g. (2-, 3-, or 4-)methylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl, (2-, 3-,or 4-)isopropylbenzoyl, (2-, 3-, or 4-)tert-butylbenzoyl,2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl,2,4,6-trimethylbenzoyl, pentamethylbenzoyl, α-phenyl-(2-, 3-, or4-(toluyl, 2-, 3-, or 4-phenethylbenzoyl, 2-, 3-, or 4-nitrobenzoyl,(2,4-, 2,5-, or 3,5-)dinitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl,2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono-esterifiedphthaloyl, e.g. ##SPC92##

isophthaloyl, e.g. ##SPC93##

or terephthaloyl, e.g. ##SPC94##

(1- or 2-)naphthoyl; and substituted naphthoyl, e.g. (2-, 3-, 4-, 5-,6-, or 7-)-methyl-1-naphthoyl, (2-or 4-)ethyl-1-naphthoyl,2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl,6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl,8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-naphthoyl,4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7- or 8)-methyl-1-naphthoyl,4-ethyl-2-naphthoyl, and (5- or 8-)-nitro-2-naphthoyl. There may beemployed, therefore, benzoyl chloride, 4-nitrobenzoyl chloride,3,5-dinitrobenzoyl chloride, and the like, i.e. R₃₉ Cl compoundscorresponding to the above R₃₉ groups. If the acyl chloride is notavailable, it is made from the corresponding acid and phosphoruspentachloride as is known in the art.

In step (d), the formula -CXII acetal is converted to aldehyde CXIII byacid hydrolysis, known in the art, using dilute mineral acids, acetic orformic acids, and the like. Solvents such as acetone, dioxane, andtetrahydrofuran are used.

For steps (e) through (h) it is optional whether R₄₂ be hydrogen or a"blocking group" as defined below. For efficient utilization of theWittig reagent it is preferred that R₄₂ be a blocking group. If theformula-CXII compound is used wherein R₄₃ is hydrogen, the formula-CXIIIintermediates will have hydrogen at R₄₂. If R₄₂ is to be a blockinggroup, that may be readily provided prior to step (e) by reaction withsuitable reagents as discussed below.

The blocking group, R₄₁, is any group which replaces hydrogen of thehydroxyl groups, which is not attacked by nor is reactive to thereagents used in the respective transformations to the extent that thehydroxyl group is, and which is subsequently replaceable by hydrogen ata later stage in the preparation of the prostaglandin-like products.

Several blocking groups are known in the art, e.g. tetrahydropyranyl,acetyl, and p-phenylbenzoyl (see Corey et al., J. Am. Chem. Soc. 93,1491 (1971)).

Those which have been found useful include (a) carboxyacyl within thescope of R₃₉ above, i.e. acetyl, and also benzoyl, naphthoyl, and thelike; (b) tetrahydropyranyl; (c) tetrahydrofuranyl; (d) a group of theformula ##EQU45## wherein R₄₈ is alkyl of one to 18 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one,2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₄₉ and R₅₀are the same or different, being hydrogen, alkyl of one to 4 carbonatoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkylof one to 4 carbon atoms, inclusive, or, when R₄₉ and R₃₀ are takentogether, --(CH₂)_(u) -- or --(CH₂)_(v) --O--(CH₂)_(w) --wherein u is 3,4, or 5, v is one, 2, or 3, and w is one, 2, or 3 with the proviso thatv plus w is 2, 3, or 4, and wherein R₅₁ is hydrogen or phenyl; or (e)--Si(A)₃ wherein A is alkyl of one to four carbon atoms, inclusive,phenyl, phenyl substituted with one or 2 fluoro, chloro, or alkyl of oneto four carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms,inclusive.

In replacing the hydrogen atoms of the hydroxyl groups with acarboxyacyl blocking group, methods known in the art are used. Thereagents and conditions are discussed above for R₄₃ on compound CXII.

When the blocking group is tetrahydropyranyl or tetrahydrofuranyl, theappropriate reagent, e.g. 2,3-dihydropyran or 2,3-dihydrofuran, is usedin an inert solvent such as dichloromethane, in the presence of an acidcondensing agent such as p-toluenesulfonic acid or pyridinehydrochloride. The reagent is used in slight excess, preferably 1.0 to1.2 times theory. The reaction is carried out at about 20°-50° C.

When the blocking group is of the formula ##EQU46## as defined above,the appropriate reagent is a vinyl ether, e.g. isobutyl vinyl ether orany vinyl ether of the formula R₄₈ --O--C(R₄₉)=CR₅₀ R₅₁ wherein R₄₈,R₄₉, R₅₀, and R₅₁ are as defined above; or an unsaturated cyclic orheterocyclic compound, e.g. 1-cyclohex-1-yl methyl ether ##SPC95##

or 5,6-dihydro-4-methoxy-2H-pyran ##SPC96##

See C. B. Reese et al., J. Am. Chem. Soc. 89, 3366 (1967). The reactionconditions for such vinyl ethers and unsaturates are similar to thosefor dihydropyran above.

When the blocking group is silyl of the formula --Si(A)₃, theformula-CXIII compound is transformed to a silyl derivative of formulaCXIII by procedures known in the art. See, for example, Pierce,"Silylation or Organic Compounds," Pierce Chemical Co., Rockford, Ill.(1968). The necessary silylating agents for these transformations areknown in the art or are prepared by methods known in the art. See, forexample, Post "Silicones and Other Organic Silicon Compounds," ReinholdPublishing Corp., New York, N.Y. (1949). These reagents are used in thepresence of a tertiary base such as pyridine at temperatures in therange of about 0° to +50° C. Examples of trisubstitutedmono-chlorosilanes suitable for this purpose includechlorotrimethylsilane, chlorotriisobutylsilane, chlorotriphenylsilane,chlorotris(p-chlorophenyl)silane, chlorotri-m-tolylsilane, andtribenzylchlorosilane. Alternately, a chlorosilane is used with acorresponding disilazane. Examples of other silylating agents suitablefor forming the formula-CXIII intermediates includepentamethylsilylamine, pentaethylsilylamine,N-trimethylsilydiethylamine, 1,1,1-triethyl-N,N-dimethylsilylamine,N,N-diisopropyl-1,1,1,-trimethylsilylamine,1,1,1-tributyl-N,N-dimethylsilylamineN,N-dibutyl-1,1,1-trimethylsilylamine,1-isobutyl-N,N,1,1-tetramethylsilylamine,N-benzyl-N-ethyl-1,1,1-trimethylsilylamine,N,N,1,1-tetramethyl-1-phenylsilylamine,N,N-diethyl-1,1-dimethyl-1-phenylsilylamine,N,N-diethyl-1-methyl-1,1-diphenylsilylamine,N,N-dibutyl-1,1,1-triphenylsilylamine, and1-methyl-N,N,1,1-tetraphenylsilylamine.

In step (e) the aldehyde group is transformed by the Wittig reaction toa moiety of the formula --CH=CR₂ G. For this purpose a phosphonium saltprepared from an organic chloride or bromide of the formula ##EQU47## isemployed, wherein G and R₂ are as defined above. These organic chloridesor bromides are known in the art or are readily prepared by methodsknown in the art. See for example the above-identified GermanOffenlegungsschrift No. 2,209,990. As to the Wittig reaction, see, forexample, U.S. Pat. No. 3,776,941 and references cited therein.

In step (f) compound CXV is obtained by deblocking if necessary. WhenC_(p) H_(2p) is a valence bond, and R₄₂ is a hindered carboxyacyl, e.g.##EQU48## R₄₁ on the phenolic hydroxy is selectively replaced withhydrogen by hydrolysis with sodium or potassium hydroxide inethanol-water. Instead of ethanol, other water-miscible solvents may besubstituted, for example 1,4-dioxane, tetrahydrofuran, or1,2-dimethoxyethane. The selective hydrolysis is preferably carried outat -15° to 25° C. Higher temperatures may be used but with some decreasein selectivity.

Total hydrolysis of R₄₂ blocking groups on compound CXIV isaccomplished, when R₄₂ is carboxyacyl, with an alkali alkoxide in analcoholic solvent, preferably sodium methoxide in methanol at atemperature from 25° C. to reflux. When R₄₂ is tetrahydropyranyl,aqueous acid, e.g. dilute acetic acid, is used at 25° to 50° C. When R₄₂is trialkylsilyl, either aqueous acid or base are used at 25° to 50° C.

Continuing with Chart L, in step (g) a Williamson synthesis is employedto obtain compound CXVI. The formula-CXV alcohol or phenol is condensedwith a haloacetate within the scope of Hal--CH₂ --COOR₁ wherein Hal ischloro, bromo, or iodo and R₁ is as defined above. Normally the reactionis done in the presence of a base such as n-butyllithium, phenyllithium,triphenylmethyllithium, sodium hydride, potassium t-butoxide, sodiumhydroxide, or potassium hydroxide.

The transformation from compound CXVI to product CXVIII may beaccomplished by any of several routes known in the art. See U.S. Pat.No. 3,711,515. Thus, by step (h), the alkenene CXVI is hydroxylated toglycol CXVII. For this purpose osmium tetroxide is a suitable reagent,for example in conjunction with N-methylmorpholine oxide-hydrogenperoxide complex (see Fieser et al., "Reagents for Organic Synthesis,"p. 690, John Wiley and Sons, Inc., New York (1967)). Thereafter, severalmethods are available for obtaining the formula-CXVIII product. In onemethod the glycol is converted to a bis(alkanesulfonic acid) ester andsubsequently hydrolyzed to CXVIII by methods known in the art (see, forexample German Offenlegungsschrift No. 1,937,676, Derwent Farmdoc No.6862R). Another method is by way of a diformate by formolysis of theglycol (see U.S. Pat. No. 3,711,515).

Still another method is by way of a cyclic ortho ester. For thispurpose, glycol CXVII is reacted with an ortho ester of the formula##EQU49## wherein R₄₆ is hydrogen, alkyl of one to 19 carbon atoms,inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive, substitutedwith zero to 3 halo atoms; and R₄₇ is methyl or ethyl. There is thenformed a cyclic ortho ester of the formula ##SPC97##

wherein C_(p) H_(2p), G, R₁, R₂ R₄₂, R₄₆, R₄₇, and ˜ are as definedabove. The reaction goes smoothly in a temperature range of -50° C. to+100° C., although for convenience 0° C. to +50° C. is generallypreferred. From 1.5 to 10 molar equivalents of the ortho ester areemployed, together with an acid catalyst. The amount of the catalyst isusually a small fraction of the weight of the glycol, say 1%, andtypical catalysts include pyridine hydrochloride, formic acid, hydrogenchloride, p-toluenesulfonic acid, trichloroacetic acid, ortrifluoroacetic acid. The reaction is preferably run in a solvent, forexample benzene, dichloromethane, ethyl acetate, or diethyl ether. It isgenerally completed within a few minutes and is conveniently followed byTLC (thin layer chromatography on basic silica gel plates).

The ortho ester reagents are known in the art or readily available bymethods known in the art. See for example S. M. McElvain et al., J. Am.Chem. Soc. 64, 1925 (1942), starting with an appropriate nitrile.Examples of useful ortho esters include:

trimethyl orthoformate,

triethyl orthoacetate,

triethyl orthopropionate,

trimethyl orthobutyrate,

triethyl orthovalerate,

trimethyl orthooctanoate,

trimethyl orthophenylacetate, and

trimethyl ortho (2,4-dichlorophenyl)acetate.

Preferred are those ortho esters wherein R₄₆ is alkyl of one to 7 carbonatoms; especially preferred are those wherein R₄₆ is alkyl of one to 4.

Next, the cyclic orthoester CXX is reacted with anhydrous formic acid toyield a diol diesters of the formula ##SPC98##

wherein C_(p) H_(2p), G, R₁ R₂, R₄₂, R₄₆, and ˜ are as defined above.

By "anhydrous formic acid" is meant that it contains not more than 0.5%water. The reaction is run with an excess of formic acid, which mayitself serve as the solvent for the reaction. Solvents may be present,for example dichloromethane, benzene, or diethyl ether, usually not over20% by volume of the formic acid. There may also be present organic acidanhydrides, for example acetic anhydride, or alkyl orthoesters, forexample trimethyl orthoformate, which are useful as drying agents forthe formic acid. Although the reaction proceeds over a wide range oftemperatures, it is conveniently run at about 20°-30° C. and is usuallycompleted within about 10 minutes.

Finally, the diol diester CXXI is converted to product CXVIII by methodsknown in the art, for example by hydrolysis in the presence of a base inan alcoholic medium. Examples of the base are sodium or potassiumcarbonate or sodium or potassium alkoxides including methoxides orethoxides. The reaction is conveniently run in an excess of thesolvolysis reagent, for example methanol or ethanol. The temperaturerange is from -50° C. to 100° C. The time for completion of the reactionvaries with the nature of R₄₆ and the base, proceeding in the case ofalkali carbonates in a few minutes when R₄₆ is hydrogen but taking up toseveral hours when R₄₆ is ethyl, for example.

When the solvolysis proceeds too long or when conditions are too severe,ester groups at R₁ may be removed. They are, however, readily replacedby methods known in the art. For example, the alkyl, cycloalkyl, andaralkyl esters are prepared by interaction of the formula-CXVIII acidswith the appropriate diazohydrocarbon. For example, when diazomethane isused, the methyl esters are produced. Similar use of diazoethane,diazobutane, 1-diazo-2-ethylhexane, diazocyclohexane, andphenyldiazomethane, for example, gives the ethyl, butyl, 2-ethylhexyl,cyclohexyl, and benzyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by methodsknown in the art. See, for example Organic Reactions, John Wiley & Sons,Inc., New York, N.Y. Vol. 8, pp. 389-394 (1954).

An alternative method for esterification of the carboxyl moietycomprises transformation of the free acid to the corresponding silversalt, followed by interaction of that salt with an alkyl iodide.Examples of suitable iodides are methyl iodide, ethyl iodide, butyliodide, isobutyl iodide, tere-butyl iodide, cyclopropyl iodide,cyclopentyl iodide, benzyl iodide, phenethyl iodide, and the like. Thesilver salts are prepared by conventional methods, for example, bydissolving the acid in cold dilute aqueous ammonia, evaporating theexcess ammonia at reduced pressure, and then adding the stoichiometricamount of silver nitrate.

The phenyl and substituted phenyl esters are prepared by silylating theacid to protect the hydroxy groups, for example, replacing each --OHwith --O--Si--(CH₃)₃. Doing that may also change --COOH to--COO--Si--(CH₃)₃. A brief treatment of the silylated compound withwater will change --COO--Si--(CH₃)₃ back to --COOH. Procedures for thissilylation are known in the art. Then, treatment of the silylatedcompound with oxalyl chloride gives the acid chloride which is reactedwith phenol or the appropriate substituted phenol to give a silylatedphenyl or substituted phenyl ester. Then the silyl groups, e.g.,--O--Si--(CH₃)₃ are changed back to --OH by treatment with dilute aceticacid. Procedures for these transformations are known in the art.

Referring to Chart M, there are shown process steps by which theformula-CIX bicyclo hexene is transformed first to an oxetane CXXII witha fully developed side chain. ##SPC99## ##SPC100##

and ultimately to a PGE analog. In Chart M, R₄₄ is hydrogen or alkyl ofone to 4 carbon atoms, inclusive, and R₄₅ is hydrogen, alkyl of one to 4carbon atoms, inclusive, or silyl of the formula (A)₃ Si-- wherein A isas defined herein above.

In step (a) of Chart M, there is employed an aldehyde of the formula##SPC101##

wherein C_(p) H_(2p) and R₄₄ are as defined above. Such aldehydes areavailable or readily prepared by methods known in the art. Examples ofsuch compounds include: ##SPC102##

The conditions for step (a) of Chart M are essentially the same as forstep (a) of Chart L. Thereafter, step (b) for cleavage of the oxetanering, steps (c) and (d) leading to the formula-CXXV aldehyde, and theWittig reaction of step (e) are similar to and employ the sameconditions as the corresponding steps of Chart L discussed above.

Referring to step (g) of Chart M, the hydroxyl on the cyclopentane ringat the C-9 position is oxidized to an oxo group.

Oxidation reagents useful for this transformation are known in the art.A useful reagent for this purpose is the Jones reagent, i.e., acidifiedchromic acid. See J. Chem. Soc. 39 (1946). A slight excess beyond theamount necessary to oxidize the C-9 secondary hydroxy groups of theformula-CXXVII reactant is used. Acetone is a suitable diluent for thispurpose. Reaction temperatures at least as low as about 0° C. should beused. Preferred reaction temperatures are in the range 0° to -50° C. Anespecially useful reagent for this purpose is the Collins reagent, i.e.chromium trioxide in pyridine. See J. C. Collins et al., TetrahedronLett., 3363 (1968). Dichloromethane is a suitable diluent for thispurpose. Reaction temperatures of below 30° C. should be used. Preferredreaction temperatures are in the range 0° to +30° C. The oxidationproceeds rapidly and is usually complete in about 5 to 20 minutes.

Examples of other oxidation reagents useful for this transformation aresilver carbonate on Celite (Chem. Commun. 1102 (1969)), mixtures ofchromium trioxide and pyridine (J. Am. Chem. Soc. 75, 422 (1953), andTetrahedron, 18, 1351 (1962)), t-butylchromate in pyridine (Biochem. J.84, 195 (1962)), mixtures of sulfur trioxide in pyridine anddimethylsulfoxide (J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87,5661 (1965)).

Step (h) of Chart M and subsequent steps by which the product CXXX isobtained are similar to and employ the same conditions as thecorresponding steps of Chart L discussed above.

Referring next to Chart N the process steps are shown whereby aldehydeCXIII of Chart L is transformed to a 17,18-tetradehydro-PG analog CXXXVIand a 17,18-didehydro-PG analog CXXXVII.

In step (a) of Chart N, a Wittig reagent is employed which is preparedfrom a phosphonium salt of a haloalkyne of the formula

    Cl--CHR.sub.2 --C.sub.n H.sub.2n --C.tbd.C--R.sub.5

or

    Br--CHR.sub.2 --C.sub.n H.sub.2n --C.tbd.C--R.sub.5

wherein C_(n) H_(2n), R₂, and R₅ are as defined above. See, for example,U. Axen et al., Chem. Comm. 1969, 303, and ibid. 1970, 602.

Thereafter, in steps (b) to (d) and subsequent steps yielding the17,18-tetradehydro compound CXXVI, the reagents ##SPC103##

and conditions are similar to those employed for the correspondingreactions shown in Chart L.

Transformation of CXXXVI to the formula-CXXXVII compounds isaccomplished by hydrogenation of CXXXVI using a catalyst which catalyzeshydrogenation of --C.tbd.C-- only to cis--CH=CH--, as known in the art.See, for example, Fieser et al., "Reagents for Organic Syntheses," pp.566-567, John Wiley and Sons, Inc., New York (1967). Preferred isLindlar catalyst in the presence of quinoline, see Axen, referencescited.

The intermediates of Charts L, M, and N, including those compoundsrepresented by formulas CX, CXI, CXII, CXIII, CXIV, CXV, CXVI, CXVII,CXXII, CXXIII, CXXIV, CXXV, CXXVI, CXXVII, CXXVIII, CXXIX, CXXXII,CXXXIII, CXXXIV, CXXXV, and CXXXVI are frequently not isolated but useddirectly for a subsequent process step. When they are isolated, they arepurified by methods known in the art, for example partition extraction,fractional crystallization, and, preferably, silica gel columnchromatography.

The products represented by formulas CXVIII, CXXX, and CXXXVII obtainedfrom these intermediates are often a mixture of 15-α and 15-β isomers.These are separated by methods known in the art, for example, bychromatography on neutral silica gel. In some instances, particularlywhere R₂ is alkyl, the lower alkyl esters are more readily separatedthan are the corresponding acids. In those cases wherein R₁ is hydrogen,it is advantageous to esterify the mixture of acids, as withdiazomethane, to form the methyl esters, separate the two epimers, andthen, if desired, replace the carboxyl methyl with hydrogen by methodsknown in the art.

When an optically active intermediate or starting material is employed,subsequent steps yield optically active intermediates or products. Thatoptical isomer of bicyclo hexene CIX is used which will yield productCXVIII for example, in the configuration corresponding to that of thenaturally occurring prostaglandins. When the racemic form of theintermediate or starting material is employed, the subsequentintermediates or products are obtained in their racemic form.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention can be more fully understood by the following examples andpreparations:

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin-Elmer Model 421infrared spectrophotometer. Except when specified otherwise, undiluted(neat) samples are used.

Ultraviolet spectra are recorded on a Cary Model 15 spectrophotometer.

NMR spectra are recorded on a Varian A-60, A-60D, or T-60spectrophotometer using deuterochloroform solutions withtetramethylsilane as an internal standard (downfield).

Mass spectra are recorded on a CEC Model 110B Double Focusing HighResolution Mass Spectrometer or an LKB Model 9,000 GasChromatograph-Mass Spectrometer (ionization voltage 70 ev).

Circular dichroism curves are recorded on a Cary 60 recordingspectropolarimeter.

Specific rotations are determined for solutions of a compound in thespecified solvent with a Perkin-Elmer Model 141 Automatic Polarimeter.

The collection of chromatographic eluate fractions starts when theeluant front reaches the bottom of the column.

"Brine," herein, refers to an aqueous saturated sodium chloridesolution.

The A-IX solvent system used in thin layer chromatography is made upfrom ethyl acetate-acetic acid-2,2,4-trimethylpentane-water(90:20:50:100) according to M. Hamberg and B. Samuelsson, J. Biol. Chem.241, 257 (1966).

"Skellysolve-B" refers to mixed isomeric hexanes.

Silica gel chromatography, as used herein, is understood to includeelution, collection of fractions, and combination of those fractionsshown by TLC (thin layer chromatography) to contain the desired productfree of starting material and impurities.

PREPARATION 1dl-Endo-6-(1-heptenyl)-3-(1-pyrrolidyl)-bicyclo[3.1.0]hex-2-ene.

A solution of formula-XLIII endo-6-(cis- andtrans-1-heptenyl)bicyclo[3.1.0]hexan-3-one (see Example 29 of WestGermany Offenlegungsschrift No. 1,937,912, cited above) (15 g.), 25 ml.of pyrrolidine, and 200 ml. of benzene is heated under reflux whileremoving the water formed by distillation. After 2 hrs. the benzene isreplaced by 50 ml. of toluene which is then removed in vacuo to give thetitle compound. This material gives an infrared spectrum havingabsorption attributable to the enamine double bond at 1610 cm⁻ ¹ andfree of carbonyl absorption.

PREPARATION 2 Methyl m-(Chloromethyl)phenoxyacetate (Formula LIII: C_(g)H_(2g) and C_(p) H_(2p) are valence bonds in meta relationship, C_(q)H_(2q) is methylene, Hal is chloro, R₂₆ is hydrogen, and R₁₀ is methyl).

a. m-Formylphenoxyacetic Acid. To a solution of m-hydroxybenzaldehyde(48.8 g.) and sodium hydroxide (16.16 g.) in 500 ml. of water is added asolution prepared from chloroacetic acid (75 g.) and sodium hydroxide(32 g.) in 100 ml. of water. The mixture is heated under reflux for 2hrs., cooled, and the pH is adjusted to pH 1 or 2. The mixture isextracted with dichloromethane-ether and the extract is dried andconcentrated. The solid is taken up in saturated aqueous sodiumbicarbonate, extracted with ether and the aqueous phase is made acidic.The aqueous phase is extracted with dichloromethane. The organic layeris concentrated and the residue is recrystallized from water to givem-formylphenoxyacetic acid (34.0 g.) m.p. 114°-117°.

b. Methyl M-Formylphenoxyacetate. A solution of the product of step a(30.0 g.) in 400 ml. of diethyl ethertetrahydrofuran is treated with anexcess of ethereal diazomethane generated fromN-methyl-N'-nitro-N-nitro-soguanidine (32.5 g.) and 200 ml. of 30%potassium hydroxide. The organic extract is washed with 5% sodiumhydroxide, dried and concentrated to give methyl m-formylphenoxyacetate(17 g.), as a light yellow oil.

c. Methyl m-(Hydroxymethyl)phenoxyacetate. A solution of the product ofstep b (30.0 g.) in 200 ml. of methanol, cooled in an ice bath to 0°, istreated with sodium borohydride (1.55 g.) in 30 ml. of cold water. Afterthe addition, stirring is continued for 20 min., the methanol isremoved, and 60 ml. of brine is added. The aqueous phase is extractedwith ether and the ether solution is washed, first with 5% aqueoushydrochloric acid, then brine, and dried. Removal of the solvent yieldsmethyl m-(hydroxymethyl)phenoxyacetate(27.0 g.).

d. Methyl m-(Chloromethyl)phenoxyacetate. To the product of step c (27.0g.) is added 20 ml. of thionyl chloride with stirring. Following theaddition, the reaction mixture is stirred at 25° for 30 min. and atreflux for 30 min. After cooling the reaction mixture, it is dissolvedin ether and washed carefully with water, saturated aqueous sodiumbicarbonte and brine. The organic layer is dried, concentrated anddistilled to give the title compound (11.0 g.) b.p. 98°-110°/0.03 mm.

Following the procedures of Preparation 2, but replacing chloroaceticacid with 3-chloropropionic acid, there is obtained, successively,3-(m-formylphenoxy)propionic acid and its methyl ester, methyl3-[m-(hydroxymethyl)phenoxy]-propionate, and the formula-LIII compound,methyl 3-[m-(chloromethyl)phenoxy]propionate.

Alternatively, Michael addition of m-hydroxy benzaldehyde to methylacrylate, with base catalysis, and reduction of the product with sodiumborohydride gives methyl 3-[m-(hydroxymethyl)phenoxy]propionate.

PREPARATION 3 Ethyl o-(Bromomethyl)benzyloxyacetate (Formula LIII: C_(g)H_(2g) is a valence bond, C_(p) H_(2p) and C_(q) H_(2q) are methylene,C_(g) H_(2g) and C_(p) H_(2p) are in ortho relationship, Hal is bromo,R₂₆ is hydrogen, and R₁₀ is ethyl).

To a mixture of α,α'-dibromo-o-xylene (100 g.), ethyl glycolate (47 g.),and dimethylformamide (500 ml.) is added with stirring over a 1-hourperiod at 0°-5° C., 18 g. of 57% sodium hydride. The mixture is stirredfor 16 hrs. at about 25° C. and is then concentrated on a rotatingevaporator at 40°-50° C. under vacuum. The residue is diluted with oneliter of a mixture of isomeric hexanes (Skellysolve B) and diethyl ether(1:2 by volume) and the organic solution is washed successively withdilute hydrochloric acid, dilute potassium hydroxide solution, water,and brine, and is finally dried and concentrated. The residue ischromatographed on a column prepared by wet-packing 3 kg. of silica gel(Brinkman) with 6 l. of 15% ethyl acetate in Skellysolve B and 30 ml. ofabsolute ethanol. Gradient elution of the column with 16 l. of 15-35%ethyl acetate in Skellysolve B gives fractions of 400 ml. each of whichare combined on the basis of thin layer chromatography (TLC). Fromfractions 18-27 there is obtained 35 g. of the title compound. Thismaterial has λ_(max). in ethanol at 231 mμ (ε 7550) with shoulders at272 (ε 700) and 278 mμ (ε 462). It has key absorptions in its NMRspectrum at about 7.3 (apparent singlet), 4.7 (singlet), 4.64 (singlet),4.06 (singlet), 4.0-4.35 (quartet), and 1.1-1.34 (triplet) δ. It hasmass spectral peaks at 206, 199, 201, 185, and 183.

PREPARATION 4 Endo-6-(cis-4-phenyl-1-butenyl)-bicyclo-[3.1.0]hexan-3-one(Formula XLIII: G is ##SPC104##

R₃ and R₄ are hydrogen; and ˜ is endo).

a. There is first prepared (3-phenylpropyl)triphenylphosphonium bromide.A solution of 597.3 g. of 1-bromo-3-phenylpropane and 786 g. oftriphenylphosphine in 1,500 ml. of toluene is heated at reflux undernitrogen for 16 hrs., then the mixture is cooled and the solid productis separated by filtration. The solid is then slurried with toluene in aWaring blender, separated by filtration, and dried for 18 hrs. at 70° C.under reduced pressure to give 1068 g. of(3-phenylpropyl)triphenylphosphonium bromide; m.p. 210.5°-211.5° C.

b. A suspension of 314 g. of the product of step a in 3 l. of benzene isstirred at room temperature (25° C.) under nitrogen, and 400 ml. of 1.6M butyllithium in hexane is added over a 20 min. period. The mixture isheated at 35° C. for 30 minutes, then is cooled to -15° C. and asolution of 100 g. of endo-bicyclo[3.1.0]hexan-3-ol-6-carboxaldehyde3-tetrahydropyranyl ether in 200 ml. of benzene is added over a 30-min.period. This mixture is heated at 70° C. for 2.5 hrs., cooled, andfiltered. The filtrate is washed three times with water, dried oversodium sulfate, and concentrated to 170 g. of crudeendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-ol3-tetrahydropyranyl ether.

A solution of 340 g. (two runs) of this crudeendo-6-(cis-4-phenyl-1-butenyl)-bicyclo-[3.1.0]hexan-3-ol3-tetrahydropyranyl ether and 20 g. of oxalic acid in 3600 ml. ofmethanol is heated at reflux for 3.5 hrs. The mixture is cooled and themethanol is evaporated under reduced pressure. The residue is mixed withdichloromethane, and the dichloromethane solution is washed with aqueoussodium bicarbonate, dried over sodium sulfate, and concentrated to 272g. of the endo-6-(cis-4-phenyl-1-butenyl)bicyclo[3.1.0]-hexan-3-ol.

A solution of 93 g. of the aboveendo-6-(cis-4-phenyl-1-butenyl)bicyclo[3.1.0]hexan-3-ol in 2570 ml. ofacetone is cooled to -5° C. and 160 ml. of Jones reagent (in theproportions 42 g. of chromic anhydride, 120 ml. of water, and 34 ml. ofconcentrated sulfuric acid) is added over a period of 30 min. whilecooling to maintain a temperature of -5° C. The mixture is allowed tostand for 10 min. longer; then 100 ml. of isopropyl alcohol is added andthe mixture is swirled for 5 min. The mixture is then diluted with 6 l.of water and extracted several times with dichloromethane. The organiclayers are separated, washed with dilute hydrochloric acid, water,dilute aqueous sodium bicarbonate, and brine, then are dried over sodiumsulfate, combined and concentrated to 83 g. of crudeendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one.

Crude endo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]-hexan-3-one (162g., two runs) is dissolved in isomeric hexanes (Skellysolve B) andchromatographed over 5 kg. of silica gel wet-packed with Skellysolve B,eluting successively with 11 l. of Skellysolve B, 62 l. of 2.5% ethylacetate in Skellysolve B, and 32 l. of 5% ethyl acetate in SkellysolveB. The last 8 l. of the 2.5% ethyl acetate in Skellysolve B eluates andthe 32 l. of 5% ethyl acetate in Skellysolve B eluates are combined andconcentrated to 75.8 g. of the title compound; infrared absorption at3000, 1750, 1610, 1500, 1455, 1405, 1265, 1150, 778, 750 and 702 cm⁻ ¹.,N.M.R. peaks at 7.18 (singlet) and 4.75-6.0 (broad multiplet) δ.

PREPARATION 5Endo-6-(cis-5-phenyl-1-pentenyl)-bicyclo-[3.1.0]hexan-3-one. (FormulaXLIII: G is ##SPC105##

R₂ and R₉ are hydrogen; and ˜ is endo).

a. There is first prepared (4-phenylbutyl)triphenylphosphonium bromide.A solution of 145 g. of 4-phenyl-1-bromobutane and 179 g. oftriphenylphosphine in 350 ml. of toluene is heated at reflux undernitrogen for 16 hrs. The mixture is then cooled slowly and ether isadded giving a precipitate of (4-phenylbutyl)triphenylphosphoniumbromide which is washed throughly with benzene/ether and dried 18 hrs.at 50° C. under reduced pressure, 268 g., m.p. 139°-140° C.

b. A suspension of 242 g. of the product of step a in 2.3 l. of drybenzene at 25° C. is stirred and 300 ml. of 1.6 M butyllithium in hexaneis added over a 15-min. period. The mixture is stirred at 30° C. for onehour, then is cooled to 10° C. and a solution of 75 g. ofendobicyclo-[3.1.0]hexan-3-ol-6-carboxaldehyde 3-tetrahydropyranyl etherin 200 ml. of benzene is added over a 15-min. period. The mixture isheated at 65°-70° C. for 3 hours, cooled and filtered. The filtrate iswashed with water and brine, dried over sodium sulfate, and concentratedunder reduced pressure to give 117 g. of crudeendo-6-(cis-5-phenyl-1-pentenyl)-bicyclo[3.1.0]hexan-3-oltetrahydropyranyl ether showing a single spot, R_(f) 0.75, on thin layerchromatography with silica gel plates developed with 20% ethyl acetatein cyclohexane.

A solution of 117 g. of the above crudeendo-6-(cis-5-phenyl-1-pentenyl)-bicyclo[3.1.0]hexan-3-oltetrahydropyranyl ether and 6 g. of oxalic acid in 2,500 ml. of methanolis heated under reflux for 2.5 hrs. The methanol is then removed bydistillation under reduced pressure and the residue is diluted withwater and extracted with dichloromethane. The dichloromethane extractsare combined, washed with aqueous sodium bicarbonate and brine, driedover sodium sulfate and concentrated under reduced pressure to give 95.7g. of crude endo-6-(cis-5-phenyl-1-pentenyl)-bicyclo[3.1.0]hexan-3-ol.The entire crude product is chromatographed over 1.5 kg. of silica gelwet-packed with Skellysolve B, eluting successively with 5 l. ofSkellysolve B, 4 l. of 2.5%, 6 l. of 5%, 9 l. of 7.5%, 12 l. of 10%, 8l. of 15%, 10 l. of 20% and 10 l. of 30% ethyl acetate in Skellysolve B,taking 600 ml. fractions. The last fraction of 10% ethyl acetate inSkellysolve B, all the 15% and 20% ethyl acetate in Skellysolve Beluates, and the first 3 fractions of 30% ethyl acetate in Skellysolve Bare concentrated to 60.5 g. of purifiedendo-6-(cis-5-phenyl-1-pentenyl)bicyclo[3.1.0]hexan-3-ol.

A solution of 60.5 g. of the above purified alcohol in 1,600 ml. ofacetone is cooled to -10° C. and 103 ml. of Jones reagent is addeddropwise. After addition is complete the mixture is stirred for 10 min.at 0° C. and 65 ml. of isopropyl alcohol is added. The mixture is pouredinto 8 l. of water and extracted several times with dichloromethane. Thedichloromethane extracts are combined, washed with dilute hydrochloricacid, aqueous sodium bicarbonate and brine, dried over sodium sulfateand concentrated under reduced pressure to give 56 g. of crudeendo-6-(cis-5-phenyl-1-pentenyl)bicyclo[3.1.0]hexan-3-one. The crudeketone is slurried in Skellysolve B and chromatographed over 2,300 g. ofsilica gel wet packed in Skellysolve B, eluting successively with 6 l.of Skellysolve B, 16 l. of 2.5% ethyl acetate in Skellysolve B, thengradient elution with 5 l. of 2.5% and 5 l. of 5% ethyl acetate inSkellysolve B and finally 16 l. of 5% ethyl acetate in Skellysolve B,taking 625 ml. fractions. The last fraction of the gradient eluates andthe first 19 fractions of 5% ethyl acetate in Skellysolve B areconcentrated to give 23.6 of the title compound; infrared absorption at2980, 1745, 1600, 1490, 1450, 1260, 1145, 770, 750 and 702 cm⁻ ¹.,N.M.R. peaks at 7.17 (singlet), 6.0-5.4 (multiplet), and 5.2-4.7 (broadmultiplet) δ.

PREPARATION 6Endo-6-(1,2-dihydroxy-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-one Acetonide(Formula XXXVI wherein G is ##SPC106## R₂ and R₉ are hydrogen, R₁₁ andR₁₂ are methyl, and ˜ is endo).

a. There is first prepared the formula-LI dihydroxy compound. To asolution of endo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one(10.0 g., Preparation 4) in about 100 ml. tetrahydrofuran is added, withstirring, a solution of potassium chlorate (10.0 g.) and osmiumtetroxide (0.65 g.) in 250 ml. of water. The mixture is stirredvigorously for 5 hrs. at 50° C. Then, the cooled mixture is concentratedunder reduced pressure. The residue is extracted repeatedly withdichloromethane, and the combined extracts are dried and concentrated toan oil. This oil is chromatographed on about 1000 g. of silica gel, andeluted successively with 3 l. of 10% ethyl acetate in a mixture ofisomeric hexanes (Skellysolve B), with 5 l. of 25% ethyl acetate inSkellysolve B, and then with 50% ethyl acetate in Skellysolve B,collecting 500 ml. eluate fractions. Fractions 13-19 (50% ethyl acetate)are combined and evaporated to dryness to give dl-endo-6(1,2-dihydroxy-4-phenylbutyl)-bicyclo[3.1.0]hexane-3-one (Formula LI).

b. A solution of the product of step a (about 8.0 g.) and 700 mg. ofpotassium bisulfate in 140 ml. of acetone is stirred at 25° C. for 64hrs. Then sodium carbonate monohydrate (710 mg.) is added, and themixture is stirred 10 minutes. The acetone is evaporated at reducedpressure, and water is added. The aqueous solution is extractedrepeatedly with dichloromethane, and the extracts are combined, washedwith water, dried, and concentrated to about 9.3 g. of an oil. The oilis chromatographed on 400 g. of silica gel, being eluted with 2 l. of10% ethyl acetate in Skellysolve B, and then with 4 l. of 15% ethylacetate in Skellysolve B. The 15% ethyl acetate eluates are concentratedto about 7.4 g. of the formula-XXXVI compound,endo-6-(1,2-dihydroxy-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-oneacetonide.

PREPARATION 7 Methyl9-Bromo-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate. (FormulaLIV: C_(j) H_(2j) and C_(p) H_(2p) are valence bonds in metarelationship, C_(q) H_(2q) is methylene, Hal is bromo, R₂₆ is hydrogenand R₁₀ is methyl).

a. To a cold, stirred solution of m-vinylanisole (13.4 g.) in 40 ml. ofdiethyl ether is slowly added a solution of bromine (15.9 g.) in 60 ml.of diethyl ether. The ether solution is used directly in converting theproduct, m-(1,2-dibromoethyl)anisole to m-methoxyphenylacetylene bydehydrohalogenation (see T. H. Vaughn, J. Am. Chem. Soc. 56, 2064,1934). The ether solution above is slowly added, with vigorous stirring,to a mixture of sodium amide prepared from sodium (4.6 g.) in about 200ml. of liquid ammonia. When the reaction is complete, the volume isreduced about one-half, and an equal volume of water is cautiouslyadded. A layer containing the product is separated, washed with dilutehydrochloric acid, dried, and distilled.

b. To a solution of the product of step a above in 250 ml. ofdichloromethane, maintained at 0° C. under nitrogen, is added dropwiseover about a 1-hour period with vigorous stirring a solution of about 15ml. of boron tribromide in 200 ml. of dichloromethane. Cooling andstirring continue for one hour. When the reaction is complete as shownby TLC, there is added cautiously a solution of sodium carbonate inwater to neutralize the mixture. Thereafter, the solution is saturatedwith sodium chloride (added as a solid), and the organic phase isseparated and combined with additional ethyl acetate washings of theaqueous phase. The organic solutions are washed with brine, dried oversodium sulfate, and concentrated under reduced pressure to yield theacetylenic phenol.

c. To the product of step b (11.8 g.), is added gradually a solution ofsodium ethoxide (prepared from sodium and absolute ethanol). Thereafter,ethylene chlorohydrin (8.0 g.) is added in small portions. When all hasbeen added, the mixture is heated at reflux for about one hour or untilcompletion, then filtered hot. The combined filtrate and ethanolwashings are concentrated to remove alcohol, and the product distilledunder reduced pressure.

To the hydroxyethyl ether (16.2 g.) as obtained above, cooled to 15°-20°C., is added 20 ml. of dihydropyran and 100 ml. of diethylether, and,with stirring, 1 ml. of anhydrous diethyl ether saturated with hydrogenchloride. After the exothermic reaction has diminished, the mixture iskept at 25° C. for 15 hours. The mixture is washed with aqueous sodiumbicarbonate, water, and dried, then concentrated under reduced pressureto yield the tetrahydropyranyl ether.

d and e. To a solution of the product of step c (10 g.) in anhydroustetranydrofuran (180 ml.) at -78° C. under argon is added the equivalentmolecular amount of n-butyllithium in hexane. The resulting solution isstirred at -78° C. for an additional 30 minutes. A suspension of dryparaformaldehyde (two equivalents) in anhydrous tetrahydrofuran is addedand the mixture warmed to room temperature over a 30-min. period. It isstirred an additional 1 hour and poured into brine, then extracted withether, dried, and concentrated to yield the hydroxy compound.

f. The hydroxy compound of step e is converted to the bromo compound byfirst forming the mesyl derivative by reaction with methanesulfonylchloride (4 ml.) in pyridine (80 ml.) at -20° C. The mixture is stirred1 hour at -20° C., and then is poured into a stirred mixture of 3 normalhydrochloric acid (300 ml.) and ice water (500 ml.). This mixture isextracted with diethyl ether, the extract is washed with cold one normalhydrochloric acid and brine, then dried and concentrated. To a solutionof the residue (mesyl derivative) in dry acetone (100 ml.) is addedlithium bromide (5 g.) and the mixture stirred and heated at reflux onehour, then kept at 25° C. for 15 hours. The acetone is evaporated underreduced pressure, and the residue is extracted with diethyl ether. Theextract is washed with water and brine, then dried and concentrated. Theresidue is chromatographed on silica gel, eluting with 10% ethyl acetatein Skellysolve B. Fractions shown by TLC to contain the product arecombined and concentrated to give the formula-LX intermediate.

g. The product of step f above is converted to the correspondingcarboxylic acid and its methyl ester as follows. Thetetrahydropyranyloxy group is replaced by hydroxyl by contacting theproduct of f with a mixture of acetic acid/water/tetrahydrofuran(20/10/3) at 40° C. for 2 hours, thereafter removing solvents underreduced pressure.

The substituted glycol from above is oxidized to the acid in acetonesolution, using a slight excess of Jones reagent (21 g. chromicanhydride/60 ml. water/17 ml. conc. sulfuric acid) while cooling tomaintain a temperature of -5° to 0° C. After about 60 min., isopropylalcohol is added, the mixture is stirred for 10 min., and then pouredinto ice water. The acid product is isolated by extraction withchloroform, drying over sodium sulfate, and concentration under reducedpressure.

The acid from above is converted to the methyl ester by reaction withdiazomethane in diethyl ether at about 10°-25° C., followed byconcentration to yield the desired title compound.

Following the procedures of Preparation 7, but replacing m-vinylanisolewith methyl (o, m, or p-)vinylbenzyl ether, there are obtained,respectively, methyl9-bromo-3-oxa-4,7-inter-o-phenylene-5,6-dinor-7-nonynoate, methyl10-bromo-3-oxa-4,8-inter-m-phenylene-5,6,7-trinor-8-decynoate, andmethyl11-bromo-3-oxa-4,9-inter-p-phenylene-5,6,7,8-tetranor-9-undecynoate.

PREPARATION 8 Methyl9-Bromo-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoate(Formula LV: C_(j) H_(2j) and C_(p) H_(2p) are valence bonds in metarelationships. C_(q) H_(2q) is methylene, Hal is bromo, R₂₆ is hydrogenand R₁₀ is methyl).

A solution of methyl9-bromo-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate (2.0 g.,Preparation 7) in 10 ml. of pyridine is hydrogenated in the presence ofa 5% palladium on barium sulfate catalyst (150 mg.) at 25° C. and oneatmosphere. The resulting mixture is filtered and evaporated to aboutone-third the original volume. Four volumes of ethyl acetate is added,and the remaining pyridine is removed by addition of ice and one Nhydrochloric acid. The ethyl acetate layer is separated, washedsuccessively with one N hydrochloric acid and brine, dried, andevaporated. The residue is chromatographed on 250 g. of silica gel whichhas previously been acid-washed to pH 4 (Silicar CC₄, 100-200 mesh,Mallincrodt Co.), eluting with 3 l. of 25-75% ethyl acetate-SkellysolveB gradient, collecting 100 -ml. fractions. The fractions shown to havethe desired product free of starting material by TLC are combined andconcentrated under reduced pressure to give the title compoundcontaining the cis --CH=CH moiety.

Following the procedures of Preparation 8, but replacing methyl9-bromo-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate with methyl9-bromo-3-oxa-4,7-inter-o-phenylene-5,6-dinor-7-nonynoate, methyl10-bromo-3-oxa-4,8-inter-m-phenylene-5,6,7-trinor-8-decynoate, or methyl11-bromo-3-oxa-4,9-inter-p-phenylene-5,6,7,8-tetra-nor-9-undecyanoate(from the paragraphs following Preparation 7), there is obtained thecorresponding formula-LV enoate compounds in which cis--CH=CH-- hasreplaced --C.tbd.C--.

PREPARATION 9 Methyl9-Bromo-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-trans-7-nonenoate.(Formula LVI: C_(j) H_(2j) and C_(p) H_(2p) are valence bonds in metarelationship, C_(q) H_(2q) is methylene, Hal is bromo, R₂₆ is hydrogenand R₁₀ is methyl).

A solution of the compound represented by the formula ##SPC107##

(1.0 g., Preparation 7, step e) in 20 ml. of tetrahydrofuran is cooledto -10° C. This solution is added to a fresh solution of lithiumaluminum hydride (110% of theory) in tetrahydrofuran. The reactionmixture is stirred for 16 hours at 25° C. ambient temperature. Then,water (20 ml.) is added, and the resulting solution is acidified withone N hydrochloric acid, and then extracted with ethyl acetate. Theextract is washed successively with aqueous sodium bicarbonate solutionand brine, dried, and evaporated under reduced pressure. The residue ischromatographed on silica gel, eluting with a 25-75% ethylacetate-Skellysolve B gradient, combining fractions shown to have thedesired product by TLC, and removing solvent from those combinedfractions under reduced pressure to yield a compound represented by theformula ##SPC108##

Thereafter, following the procedures of Preparation 7, steps f throughg, there is obtained the title compound containing the trans--CH=CH--moiety.

Following the procedures of Preparation 9, but replacing that nonynoatewith the compound having the formula ##SPC109##

wherein the THP-terminated moiety is attached to the ring in ortho,meta, or para configuration, there is obtained the correspondingformula-LVI compound in which trans --CH=CH-- has replaced --C.tbd.C--.

PREPARATION 10 Optically ActiveBicyclo[3.1.0]-hex-2-ene-6-endo-carboxaldehyde

Following the procedure of Preparation 1 of U.S. Pat. No. 3,711,515,racemic bicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde is prepared frombicyclo[2.2.1]hepta-2,5-diene and peracetic acid.

The racemic compound is resolved by the procedure of Example 13 of U.S.Pat. No. 3,711,515, forming an oxazolidine as follows.

Racemic bicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde (12.3 g.) and1-ephedrine (16.5 g.) are dissolved in about 150 ml. of benzene. Thebenzene is removed under vacuum and the residue taken up in about 150ml. of isopropyl ether. The solution is filtered, then cooled to -13° C.to yield crystals of2-endo-bicyclo-[3.1.0]hex-2-en-6-yl-3,4-dimethyl-5-phenyl-oxazolidine,11.1 g., m.p. 90°-92° C. Three recrystallizations from isopropyl ether,cooling each time to about -2° C., yield crystals of the oxazolidine,2.2 g., m.p. 100°-103° C., now substantially a single isomeric form asshown by NMR.

The above re-crystallized oxazolidine (1.0 g.) is dissolved in a few ml.of dichloromethane, charged to a 20 g. silica gel column and eluted withdichloromethane. The silica gel is chromatography-grade (Merck),0.05-0.2 mm. particle size, with about 4-5 g. of water per 100 g.Fractions of the eluate are collected, and those shown by thin layerchromatography (TLC) to contain the desired compound are combined andevaporated to an oil (360 mg.). This oil is shown by NMR to be thedesired title compound, substantially free of the ephedrine, insubstantially a single optically-active isomeric form. Points on thecircular dichroism curve are (λ in nm.,θ): 350, 0; 322.5, -4,854; 312,-5,683; 302.5, -4,854; 269, 0; 250, 2,368; 240, 0; and 210, -34,600.

EXAMPLE 1 dl-Methyl7-[Endo-6-(1-heptenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-heptanoate(Formula XLIV, Chart E: G is n-pentyl; R₂, R₉, and R₂₆ are hydrogen; R₁₀is methyl; Z' is ##SPC110##

and ˜ is alpha and endo).

A. A solution prepared fromendo-6-(1-heptenyl)-3-(1-pyrrolidyl)-bicyclo[3.1.0]hex-2-ene(Preparation 1, 5.0 g.) and methyl m-(chloromethyl)-phenoxyacetate(Preparation 2, 4.4 g.) in 60 ml. of dioxane is stirred under a nitrogenatmosphere at about 25° C for 2 days and then heated under reflux for 7hrs. To the reaction mixture is added water. The solution is heated on asteam bath, cooled and extracted with ether. The extract is washed,first with dilute (about 5% hydrochloric acid, then brine, and dried andconcentrated. The residue is chromatographed on 700 g. of silica gelprepared with 20% ether-isomeric hexane mixture (Skellysolve B) andeluted with 1.5 l. of 20% ether-Skellysolve B, 1.5 l. of 25%ether-Skellysolve B, and 1.5 l. of 30% ether-Skellysolve B, collecting100-ml. fractions. Fractions 25-31 give the title compound (1.7 g.).

B. Alternate synthesis. - A solution of potassium tert-butoxide (9.0 g.)in 500 ml. of nitrogen-purged tetrahydrofuran is added dropwise during45 min. to a stirred solution of the formula-XLIII bicyclo olefin,endo-6-(1-heptenyl)bicyclo[3.1.0]hexan-3-one (see Example 9 of WestGermany Offenlegungsschrift No. 1,937,912, cited above) (10.0 g.), andmethyl m-(chloromethyl)phenoxyacetate (Preparation 2, 13 g.) in 250 ml.of tetrahydrofuran under nitrogen at 25° C. The resulting mixture isacidified at once with 120 ml. of 5% hydrochloric acid, and then isconcentrated under reduced pressure below 40° C. to remove most of thetetrahydrofuran. Water (400 ml.) is added to the residue, and themixture is extracted with three 400-ml. portions of ethyl acetate. Thecombined extracts are washed successively with aqueous sodiumthiosulfate solution and brine, dried, and concentrated under reducedpressure. The residue is chromatographed over 4 kg. of silica gelwet-packed with 20% ether-isomeric hexane mixture (Skellysolve B) andeluted with ether-Skellysolve B mixtures having 20-30% ether. Fractionsshown by TLC to contain the desired alkylation product are combined toyield the formula-XLIV (Chart E) alkylated olefin title compound.

Following the procedure of Example 1-B but replacing the formula-XLIII(Chart E) endo-6-(1-heptenyl)bicyclo[3.1.0]hexan-3-one with thecorresponding bicyclo olefins prepared by reaction of the-tetrahydropyranyl ether ofendo-bicyclo[3.1.0]hexan-3-ol-6-carboxaldehyde with intermediatequaternary phosphonium halides (see above-cited West GermanyOffenlegungsschrift No. 1,937,912) prepared from 1-bromobutane,1-chloropentane, 1-bromoheptane, and 1-chlorooctane, there are obtainedthe corresponding formula-XLIV alkylated olefin compounds wherein G isstraight chain alkyl of 3, 4, 6, and 7 carbon atoms, respectively.

Also following the procedure of Example 1-B but employing insteadformula-XLIII bicyclo olefins prepared from 1-bromo-2-fluorobutane,1-chloro-2-fluoro-pentane, 1-bromo-2-fluorohexane,1-bromo-2-fluoroheptane, and 1-chloro-2-fluorooctane, there are obtainedthe corresponding formula-XLIV alkylated olefin compounds wherein G isstraight chain alkyl of 3 to 7 carbon atoms, inclusive, with a fluorosubstituent at the 1-position.

Also following the procedure of Example 1-B but employing, instead,formula-XLIII bicyclo olefins prepared from primary bromides of theformula R₂₇ --(CH₂)_(b) --CH₂ Br, wherein b is one, 2, 3, or 4, and R₂₇is isobutyl, tert-butyl, 3,3-difluorobutyl, 4,4-difluorobutyl,4,4,4-trifluorobutyl, and 3,3,4,4,4-pentafluorobutyl, there are obtainedcompounds corresponding to the formula-XLIV product of Example 1-B withR₂₇ --(CH₂)_(b) --CH=CH-- in place of the 1-heptenyl moiety.

Also following the procedure of Example 1-B but employing, instead,formula-XLIII bicyclo olefins prepared from primary bromides of theformula CH₃ --(CH₂)_(c) --CR₂₁ R₂₂ --CH₂ Br wherein c is 2, 3, or 4, andR₂₁ and R₂₂ are methyl or ethyl, e.g. CH₃ --(CH₂)₂ --C(C₂ H₅)₂ --CH₂--Br, CH₃ --(CH₂)₃ --CH(CH₃)--CH₂ --Br, CH₃ --(CH₂)₃ --CH(C₂ H₅)--CH₂Cl, CH₃ --(CH₂)₃ --C(CH₃)₂ --CH₂ --Br, and CH₃ --(CH₂)₃ --C(CH₃)(C₂H₅)--CH₂ Br, there are obtained the corresponding formula-XLIV alkylatedolefin compounds wherein G is mono- or di-substituted at the 1-positionwith methyl or ethyl.

Also following the procedure with Example 1-B but employing, instead,formula-XLIII bicyclo olefins prepared from α-bromotoluene,(2-bromoethyl)benzene, (5-chloropentyl)-benzene, (6-bromohexyl)benzene,and (7-iodoheptyl)benzene; from (1-chloroethyl)-benzene,(1-bromopropyl)benzene, (2-bromopropyl)benzene, (3-chloropentyl)benzene,(4-bromopentyl)benzene, (6-bromononyl)benzene and (7-bromononyl)benzene;from 1-bromo-2-phenylpropane, 1-bromo-2-methyl-2-phenylpropane,1-chloro-2-ethyl-3-phenylpropane, 1-bromo-2-methyl-4-phenylbutane, and1-bromo-2,2-dimethyl-5-phenylpentane; from α-bromo-m-xylene,α-chloro-p-ethyltoluene, α-bromo-p-chlorotoluene,α'-chloro-α,α,α-trifluoro-m-xylene, 1-(2-bromoethyl)-4-fluorobenzene,1-(5-bromopentyl)-2-chlorobenzene,4-(3-iodopropyl)-1,2-dimethoxybenzene, and1-(3-bromohexyl)-2,4,6-trimethylbenzene; and from(2-bromo-1-fluoroethyl)benzene, (2-bromo-1-fluoropropyl)benzene,(2-chloro-fluoro-1-methylpropyl)benzene,(5-bromo-4-fluoropentyl)benzene, (7-iodo-6-fluoropentyl)benzene,(4-bromo-3,3-difluorobutyl)benzene, and(6-bromo-5,5-difluorohexyl)benzene, there are obtained the correspondingformula-XLIV alkylated olefin compounds wherein G is ##SPC111##

including compounds wherein C_(t) H_(2t) is substituted with one or 2fluoro atoms.

Also following the procedure of Example 1-B, but using formula-XLIIIbicyclo olefins obtained from the secondary bromides of the formula##EQU50## wherein G and R₂ are as defined above, R₂ being alkyl, thereare obtained formula-XLIV alkylated olefins corresponding to the productof Example 1-B with ##EQU51## in place of the 1-heptenyl moiety.

Also following the procedure of Example 1-B, but using formula-XLIIIbicyclo olefins obtained from bicyclo[3.1.0]-hexane reactants with##EQU52## in place of ##EQU53## wherein R₉ is as defined above, there isobtained formula-XLIII alkylated olefins corresponding to the product ofExample 1-B with ##EQU54## in place of the 1-heptenyl moiety.

Also following the procedure of Example 1-B, but using formula-XLIIIbicyclo olefins obtained from bicyclo-[3.1.0]hexane reactants with##EQU55## in place of ##EQU56## and primary and secondary bromides ofthe formula ##EQU57## (as above defined), there are obtained formula-LIValkylated olefins corresponding to the product of Example 1-B with##EQU58## in place of the 1-heptenyl moiety.

Also following the procedure of Example 1-B but using a larger amount ofpotassium tert-butoxide (16 g.) and maintaining the reaction mixture for8 hrs. at 25° C. before addition of hydrochloric acid, a product isobtained which contains substantial amounts of both the above described2α-yl isomer and the corresponding 2β-yl isomer. These isomers areseparated by the above-described silica gel chromatography.

Also following the procedure of Example 1-B but using exo formula-XLIIIbicyclo olefins in place of the endo reactant of Example 1-B, there areobtained the corresponding exo formula-XLIV alkylated olefins.

Also following the procedure of Example 1-B but replacing the methylm-(chloromethyl)phenoxyacetate alkylating agent with the formula-LIIIand -LIV compounds, methyl 3-[m-chloromethyl)phenoxy]propionate, methyl9-bromo-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate, and methyl10-bromo-3 -oxa-4,8-inter-m-phenylene-5,6,7-trinor-8-decynoate, thereare obtained alpha and beta, exo and endo, formula-XLIV alkylatedolefins corresponding to the product of Example 1-B with ##SPC112##

replaced with ##SPC113## ##SPC114##

respectively. In the same manner, but using, according to Example 1-B,other esters of the above-described formula-LIII and -LIV alkylatingagents within the scope of R₁₀ as above-defined, e.g., the isopropyl,tert-butyl, octyl, cyclohexyl, benzyl, and phenyl esters, there areobtained the corresponding formula-XLIV esters.

Also following the procedure of Example 1-B, but using in combinationeach of the above-described alternative formula-XLIII bicyclo olefinsand each of the above-described alternative formula-LIII or -LIVomega-halo alkylation agents, there are obtained formula-XLIV alkylatedolefins corresponding to the product of Example 1-B but differenttherefrom with respect to both the carboxylate-terminated side chain andthe side chain attached to the cyclopropane ring in the product.

Also following the procedure of example 1-B, but using in place of theformula-LIII halo alkylating agent of that Example, each of the otheralkylating agents within the scope of ##EQU59## as above defined, i.e.,alkylating agents of formulas LIII and LIV as above-described, there areobtained alpha and beta exo and endo formula-XLIV compoundscorresponding to the product of Example 1-B with each of the other##EQU60## side chains in place of the ##SPC115##

side chain of the Example 1-B product. For example, using asformula-LIII alkylating agents in the Example 1-B procedure, thefollowing compounds wherein Et is ethyl; ##SPC116##

there are obtained exo and endo, alpha and beta, formula-XLIV alkylatedbicyclo[3.1.0]hexanes each having a carboxylate-terminated side chaincorresponding to one of the specific omega-halo alkylating agents. Forexample, the side chain will be alpha or beta ##SPC117##

when the alkylating agent is ##SPC118##

Also following the procedure of Example 1-B, but using in combinationeach of the alternative alkylating formula-LIII and -LIV agents withinthe scope of ##EQU61## including the specific examples of those justmentioned, and each of the above-described formula-XLIII alternativebicyclo[3.1.0]hexane olefin reactants, there are obtained formula-XLIVexo and endo, alpha and beta, compounds corresponding to the products ofExample 1-B, but different therefrom with respect to both thecarboxylate-terminated side chain and the side chain attached to thecyclopropane ring of the product. In the same manner, alternativealkylating agents within the scope of ##EQU62## wherein R₁₀ is otherthan ethyl, e.g., methyl, isopropyl, tert-butyl, octyl, cyclohexyl,benzyl, phenyl, and β,β,β-trichloroethyl are used.

EXAMPLE 2 dl-Methyl7-[Endo-6-(1,2-dihydroxyheptyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-heptanoate(Formula XLV, Chart E: G' is n-pentyl; R₂, R₉, and R₂₆ are hydrogen; R₁₀is methyl; Z' is ##SPC119##

and ˜ is alpha and endo).

Refer to Chart E. To a solution of dl-methyl7-[endo-6-(1-heptenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-heptanoate(Example 1, 1.7 g.) in 30 ml. of tetrahydrofuran at 50° is added withstirring osmium tetroxide (200 mg.) followed by potassium chlorate (1.2g.) and 15 ml. of water. The reaction mixture is maintained at 50° for 2hrs., cooled, the tetrahydrofuran is removed, and the aqueous phase isextracted with dichloromethane. The organic layer is dried andconcentrated and the residue is chromatographed on 200 g. of silica gel.The column is eluted with 1 l. of 35% ethyl acetate-benzene and 1 l. of40% ethyl acetate-benzene, collecting 30-ml. fractions. Fractions 26-30contain one isomer (faster moving, less polar) of the title compound(350 ml.). Fractions 32-37 contain the other slower-moving (more polar)isomer (450 mg.). These materials show infrared spectral absorption at330 cm⁻ ¹.

Following the procedure of Example 2 but using the hex-2β-yl isomer inplace of the hex-2α-yl isomer of the bicyclo reactant, dl-methyl7-[endo-6-(1,2-dihydroxyheptyl)-3-oxobicyclo[3.1.0]hex-2β-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-heptanoateis obtained.

Also following the procedure of Example 2, each of the formula-XLIV exoand endo, alpha and beta, saturated and acetylenic bicyclo[3.1.0]hexaneesters defined above after Example 1 is oxidized to mixtures of thecorresponding isomeric formula-XLV dihydroxy compounds.

EXAMPLE 3 dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ Methyl Ester(Formula XVI: C_(g) H_(2g) and C_(p) H_(2p) are valence bonds in metalrelationship, G is n-pentyl,Q is ##EQU63## R₁ is methyl, and ˜ is alpha)and dl-15-Beta-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ MethylEster ##EQU64##

Refer to Chart E. To a solution of the formula-XLV dihydroxy compounddl-methyl7-[endo-6-(1,2-dihydroxyheptyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-heptanoate(800 mg. of a mixture of the slower and faster moving isomers of Example2) in 10 ml. of pyridine, cooled to 0°, is added 1.2 ml. ofmethane-sulfonyl chloride. The reaction mixture is stirred for 2 hrs.and 20 g. of ice is added. The mixture is extracted withether-dichloromethane (1:1) and the organic layer is washed successivelywith dilute hydrochloride acid, water, saturated aqueous sodiumbicarabonate, and brine, dried, and concentrated. The residue,containing the bismesylate, is treated with 15 ml. of acetone and 10 ml.of water and stirred for 8-16 hrs. at 25°. The acetone is removed invacuo and the remaining solution is extracted with dichloromethane. Theextract is dried and concentrated and the residue is chromatographed on150 g. of silica gel using 500 ml. ethyl acetate followed by 3% methanolethyl acetate as eluting solvent while collecting 30-ml. fractions.Fractions 15-24 are combined and concentrated to yield the 15-β PGE₁title compound (50 mg.); mass spectral peak at 404; ultravioletabsorption at 216 (ε = 8100), 264 (ε = 1100), 272 (ε = 1600) and 278 (ε= 1500) mμ. Fractions 26-35 are combined and concentrated to yield aresidue which is re-chromatographed on 10 g. of silica gel using thesame solvent system and collecting 1.5 ml. fractions. Fractions 22-29are combined and concentrated to give the PGE₁ title compound (75 mg.);mass spectral peak at 404; ultraviolet absorption at 216 (ε = 7700),264, 272 (ε = 1500), and 278 (ε = 1400) mμ.

Following the procedures of Example 3, each of the formula-XLVdl-endo-1,2-dihydroxy oxa-phenylene esters following Example 2 istransformed to the corresponding dl-endo-1,2-dimesyloxy oxa-phenyleneester, and thence to the corresponding PGE type compound or its isomers.

Also following the procedures of Example 3, each of the formula-XLV anddl-exo-1,2-dihydroxy-oxa-phenylene esters corresponding to the abovedl-endo-1,2-dihydroxy esters is transformed to the correspondingdl-exo-1,2-dimesyloxy ester, and thence to the corresponding PGE typecompound or its isomers.

By the above-outlined procedures, following the steps of Chart E, thereare obtained the specific PGE-type esters represented by figures XVI andXVIII, e.g. the esters of the dl-oxa-phenylene PGE₁ compounds and5,6-dehydro-PGE₂ compounds, including their 8-iso and 15-epi (β) forms.For example,dl-5,6-dehydro-3-oxa-3,7-inter-m-phenylene-18-phenyl-4,19,20-trinor-PGE.sub.2methyl ester and its 15-epimer are obtained from dl-methyl7-[endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate(Example 10 hereinafter) by way of the dihydroxy and bis(mesylate)intermediates of Chart E, following Example 3, as represented by thefollowing formulas: ##SPC120##

Also following the procedure of Example 3, but replacing methanesulfonylchloride with an alkanesulfonyl chloride or bromide or with analkanesulfonic acid anhydride, wherein the alkane moiety contains 2 to 5carbon atoms inclusive, there is obtained from each dihydroxy compoundthe corresponding bis(sulfonic acid) esters encompassed by formula XLVI.

In each of the above the in Example 3, the monosulfonic acid ester isalso obtained as a byproduct, which is reacted with additionalalkanesulfonyl halide or alkanesulfonic acid anhydride to give thecorresponding bis(sulfonic acid) ester and thence recycled back toadditional formula-XLVII product.

For satisfactory yields of the bis-sulfonic acid ester, R₁₀ is nothydrogen. Those intermediate compounds in which R₁₀ is haloethyl, e.g.,β,β,β-trichloroethyl, are especially useful in the sequence of reactionsleading to the acid form of the prostaglandin-like products. Each of theexo and endo, alpha and beta, saturated and unsaturated oxa-phenylenebis(alkanesulfonic acid) esters is transformed to the correspondingoxa-phenylene PGE type compound encompassed by formula-XLVII.

EXAMPLE 4 dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub.α MethylEster and dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub.β MethylEster (Formula XX: C_(g) H_(2g) and C_(p) H_(2p) are valence bonds inmeta relationship, G is n-pentyl, Q is ##EQU65## R₁ is methyl, and ˜ isalpha for the carboxyl-containing moiety and either alpha or beta forthe ring hydroxyl).

Refer to Chart A. A solution ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ methyl ester (Example3, 300 mg.), 20 ml. of tetrahydrofuran, 2.0 ml. of hexamethyldisilazane,and 0.15 ml. of trimethylsilyl chloride is stirred at 25° for 20 hrs.The reaction mixture is concentrated in vacuo, benzene is added, thesolution concentrated and this procedure is repeated. The residue isdissolved in 10 ml. of methanol, cooled in an ice-methanol bath, andsodium borohydride (60 mg.) in 20 ml. of cold water is added dropwise.The methanol is removed and the aqueous phase is extracted withdichloromethane, and the resulting dichloromethane solution is dried andconcentrated in vacuo. The residue is chromatographed on 45 g. of silicagel using 70 ml. of ethyl acetate and then a gradient of 0-8% methanolethyl acetate as eluting solvent, collecting 10-ml. fractions. Fractions22-36 are combined and concentrated to yield the PGF₁.sub.α -type titlecompound (100 mg.); mass spectral peak for tris-trimethylsilylderivative at 622. Fractions 37-42 are combined and concentrated toyield a residue which is chromatographed on a preparative silica gelplate using 5% methanol-methylene chloride as eluting solvent. From theplate is obtained the PGF₁.sub.β -type title compound (25 mg.); massspectral peak for tris-trimethylsilyl derivative at 622.

Following the procedure of Example 4,dl-3-oxa-4,7-inter-o-phenylene-5,6-dinor-PGE₁ ethyl ester (Example 8hereinafter) is transformed todl-3-oxa-4,7-inter-o-phenylene-5,6-dinor-PGF₁.sub.α and -PGF₁.sub.βethyl esters.

Also following the procedure of Example 4,dl-5,6-dehydro-3-oxa-3,7-inter-m-phenylene 18-phenyl-4,19-20-trinor-PGE₂methyl ester (following Example 3) is transformed to the correspondingPGF₂.sub.α and PGF₂.sub.β type compounds.

Also following the procedure of Example 4, the alkyl ester and free acidforms of formula-XX to -XXIII oxa-phenylene PGF compounds in theirvarious spatial configurations, e.g., the PGF₁.sub.α, PGF₁.sub.β,PGF₂.sub.α, PGF₂.sub.β, trans-5,6-dehydro-PGF₁.sub.α and -PGF₁.sub.βtype compounds and their 8-iso and 15-beta isomers, are prepared byreduction of the corresponding formula XVI-to -XIX PGE-type alkyl esteror free acid, including those described above after Example 3.

EXAMPLE 5 dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ formula-XXIV:C_(g) H_(2g) and C_(p) H_(2p) are valence bonds in meta relationship, Gis n-C₅ H₁₁,Q is ##EQU66## R₁ is hydrogen; and ˜ is alpha).

Refer to Chart A. A solution ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ methyl ester (Example3, 300 mg.), 4 ml. of tetrahydrofuran and 4 ml. of 0.5 N hydrochloricacid is left standing at 25° for five days. Brine solution anddichloromethane-ether (1:3) are added and the mixture is stirred. Theorganic layer is separated, dried and concentrated. The residue isdissolved in ether which is washed with saturated aqueous sodiumbicarbonate, dried and concentrated. The aqueous phase is quicklyacidified with hydrochloric acid and extracted with dichloromethanewhich in turn is dried and concentrated. The residue is again dissolvedin ether, extracted with aqueous sodium bicarbonate, and the aqueousphase is worked up as reported above. This procedure is repeated oneadditional time to yield the title compound (120 mg.). This material hasmass spectral peaks at 372, 354, 189, and 185; and λ max., in ethanol,215 mμ (ε 12,400), 272 (ε 2250) and 278 (ε 2150).

Following the procedure of Example 5, the formula XIV-to -XIX PGEcompounds in their various spatial configurations described afterExample 3 are transformed to the corresponding formula XXIV-to -XXVIIPGA compounds, either as esters or as free acids.

EXAMPLE 6 dl-Ethyl7-[Endo-6-(1-heptenyl)-3-oxobicyclo-[3.1.0]hex-2α-yl]-3-oxa-4,7-inter-o-phenylene-5,6-dinor-heptanoate(Formula-XLIV: G is n-pentyl; R₂, R₉, and R₂₆ are hydrogen; R₁₀ isethyl; Z' is ##SPC121##

and ˜ is alpha and endo).

The enamine of the formula-XLIII bicyclo-olefin is first prepared asfollows. A mixture of endo-6-(cis- andtrans-1-heptenyl)-bicyclo[3.1.0]hexan-3-one (10 g.), benzene (200 ml.),and pyrrolidine (15 ml.) is heated at reflux under a Dean-Stark watertrap for 2 hrs. Thereafter about 140 ml. of distillate is taken off overa period of about 30 min. To the remaining liquid is added 100 ml. oftoluene and the mixture is concentrated on a rotating evaporator undervacuum. A second portion of toluene (50 ml.) is added, and the mixtureconcentrated to give the enamine residue.

The above enamine, together with ethyl o-(bromomethyl)-benzyloxyacetate(Preparation 3 above, 15 g.), and dry tetrahydrofuran (200 ml.) isheated at reflux for 4 hrs. and thereafter stirred at about 25° C. for16 hrs. Water (25 ml.) is added and the mixture heated for 20 min. on asteam bath. Thereafter, the volatiles are removed under vacuum, theresidue is diluted with ether, and the organic solution is washedsuccessively with dilute acid, water, dilute base, water, and brine, andfinally dried and concentrated under vacuum. The residue ischromatographed on a column prepared by wet-packing 1300 g. of silicagel (E. Merck) with 2.5 l. of 25% diethyl ether in Skellysolve B and 13ml. of absolute ethanol. The column is eluted with 2 l. of 25% ether inSkellysolve B and then gradient-eluted with 8 l. of 25-50%ether-Skellysolve B. Fractions of about 200 ml. are combined on thebasis of TLC data. From fractions 24-31 there is obtained 2.9 g. of thedesired formula-XLIV title compound as a mixture of cis and trans forms.This material has key absorptions in its NMR spectrum at about 7.21(apparent singlet), 5.38-5.8 (multiplet), 4.62 (singlet), 4.06(singlet), and 4.0-4.35 (quartet) δ. It has mass spectral lines at 398and 294.

EXAMPLE 7 dl-Ethyl7-[endo-6-(1,2-dihydroxyheptyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-4,7-inter-o-phenylene-5,6-dinorheptanoate (Formula-XLV: G' is n-pentyl; R₂, R₉, and R₂₆ are hydrogen;R₁₀ is ethyl; Z' is ##SPC122##

and ˜ is alpha and endo).

Refer to one E. To a solution of dl-ethyl7-[endo-6-(1-heptenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-4,7-inter-o-phenylene-5,6-dinor-heptanoate,as a mixture of its isomers (Example 6, 2.8 g.) in dry tetrahydrofuran(150 ml.) at 50° C. is added 0.15 g. of osmium tetroxide followed by 2.8g. of potassium chlorate in 60 ml. of water. The mixture is stirredvigorously at 50° C. for about 1.5 hrs. and is then concentrated undervacuum. The residue is extracted with dichloromethane. The extract iswashed with water and brine, and then finally dried and concentratedunder vacuum. The residue is chromatographed on a column prepared bywet-packing 500 g. of silica gel (E. Merck) with 1 liter of 50% ethylacetate in Skellysolve B and 5 ml. of absolute ethanol. The column iseluted with 1 l. of 50% ethyl acetate in Skellysolve B and then gradienteluted with 4 l. of 50-75% ethyl acetate in Skellysolve B. Fractions of100 ml. each are combined on the basis of TLC data. From fractions 12-29there is obtained 2.6 g. of the title compound.

EXAMPLE 8 dl-3-Oxa-4,7-inter-o-phenylen-5,6-dinor-PGE₁ Ethyl Ester(Formula-XIV: C_(g) H_(2g) is a valence bond, C_(p) H_(2p) are in orthorelationship, G is n-pentyl, Q is ##EQU67## R₁ is ethyl, and ˜ is alpha)and dl-15-Beta-3-oxa-4,7-inter-o-pnenylene-5,6-dinor-PGE₁ Ethyl Ester##EQU68##

Refer to Chart E. The formula-XLVI bismesylate is first prepared asfollows. To a mixture of dl-ethyl7-[endo-6-(1,2-dihydroxyhepthyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-4,7-inter-o-phenylene-5,6-dinor-heptanoate(Example 7, 2.6 g.) and 30 ml. of dry pyridine at 0° C. is added, withstirring, 2.7 ml. of methanesulfonyl chloride over a one-minute period.The mixture is stirred at 0° C. for 2.5 hrs., then cooled to about -10°C. and diluted with 2 ml. of water added dropwise over a 5-minuteperiod. Ice (20 g.) is added, and, after stirring the mixture for 5min., about 150 ml. of ether-dichloromethane (3:1) is added. The organicsolution was washed successively with dilute hydrochloric acid, water,dilute sodium bicarbonate solution, and brine, and finally dried andconcentrated under vacuum to yield a mixture of the mesylates.

The residue of mesylates is converted to the PGE-type product bycontacting with a mixture of acetone (100 ml.) and water (50 ml.) atabout 25° C. for 16 hrs. Additional water (100 ml.) is added and themixture concentrated under vacuum to remove acetone. The residue isextracted with a mixture of ether-dichloromethane (3:1) and the organicextract is washed with dilute sodium bicarbonate solution and brine,then dried and concentrated under vacuum. The residue (2.5 g.) ischromatographed on a column prepared by wet-packing 500 g. of silica gel(E. Merck) with one liter of ethyl acetate and 5 ml. of absoluteethanol. The column is eluted with 2.6 liters of ethyl acetate, then 400ml. of 2% ethanol in ethyl acetate, then 500 ml. of 4% ethanol in ethylacetate and finally with 2 liters of 10% ethanol in ethyl acetate,collecting fractions of 100 ml. Fractions are combined on the basis ofTLC data.

From fractions 8-14 is obtained 350 mg. of the 15-β PGE₁ title compound.This material has λ_(max). 279 mμ (ε 19,400) in alcoholic potassiumhydroxide; key absorptions in the NMR spectrum at about 7.2 (apparentsinglet), 5.25-5.48 (multiplet), 4.58 (singlet), 5.25-5.48 (multiplet),4.58 (singlet) 4.06 singlet, and 4.0-4.35 (quartet) δ; and mass spectralpeaks at 414, 396, 310, and 292.

From fractions 18-37 is obtained 496 mg. of the PGE₁ title compound.This material has λ_(max). 279 mμ (ε 21,750) in alcoholic potassiumhydroxide; key absorptions in the NMR spectrum at about 7.18 (apparentsinglet), 5.25-5.41 (multiplet), 4.58 (singlet), 4.02 (singlet), and3.99-4.34 (quartet) δ; and mass spectral peaks at 414, 396, 310, and292.

EXAMPLE 9 dl-Methyl9-[Endo-6-(1,2-dihydroxy-2-methylheptyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoateAcetonide (Formula-XXXVII, Chart D: G is n-pentyl; J' is ##SPC123##

R₉ and R₂₆ are hydrogen; R₂, R₁₀, R₁₁, and R₁₂ are methyl; and ˜ is endoand alpha).

Refer to the sequence of reactions from formula-L to formula XXVI, andto Chart D.

a. There is first prepared the formula-XLIII olefin. Following theprocedure for the Wittig synthesis in Examples 27, 28, and 29 of WestGermany Offlegungsschrift 1,937,912, cited above, but employingtetrahydropyranyloxy ether ofendo-bicyclo[3.1.0]hexan-3-ol-6-carboxaldehyde and the Wittig ylide of2-chloroheptane, there is obtaineddl-endo-6-(2-methyl-1-heptenyl)-3-oxobicyclo[3.1.0]-hexan-3-one.

b. To a solution of the product of step a above (approximately 10.0 g.)in water is added a solution of potassium chlorate (10.0 g.) and osmiumtetroxide (0.65 g.) in 250 ml. of water. The mixture is stirredvigorously for 5 hrs. at 50° C. Then, the cooled mixture is concentratedunder reduced pressure, the residue is extracted repeatedly withdichloromethane, and the combined extracts are dried and evaporated. Theresidue is chromatographed on about 1000 g. of silica gel, and elutedsuccessively with 3 l. of 10% ethyl acetate in a mixture of isomerichexanes (Skellysolve B), with 5 l. of 25% ethyl acetate in SkellysolveB, and then with 50% ethyl acetate in Skellysolve B, collecting 500 ml.eluate fractions. Fractions shown by TLC to contain the desired productare combined and evaporated to dryness to give the formula-LI product,dl-endo-6-(1,2-dihydroxy-2-methylheptyl)bicyclo[3.1.0]hexan-3-one.

c. A solution of the product of step b above (about 8,0 g.) and 700 mg.of potassium bisulfate in 140 ml. of acetone is stirred at 25° C. for 64hrs. Then, sodium carbonate monohydrate (710 mg.) is added, and themixture is stirred 10 min. The acetone is evaporated at reducedpressure, and water is added. The aqueous solution is extractedrespectedly with dichloromethane, and the extracts are combined, washedwith water, dried, and evaporated. The residue is chromatographed on 400g. of silica gel, being eluted with 2 l. of 10% ethyl acetate inSkellysolve B, and then with 4 l. of 15% ethyl acetate in Skellysolve B.The 15% ethyl acetate eluates are evaporated to give the formula-XXXVIketal, dl-endo-6-(1,2-dihydroxy-2-methylheptyl)bicyclo[3.1.0]hexan-3-oneacetonide.

d. To prepare the formula-XXXVII compound (Chart D), the ketal above isalkylated following the procedure of Example 1-B, but using theformula-XXXVI ketal above instead of the formula-XLIII bicyclo olefin,and, replacing methyl m-(chloromethyl)phenoxyacetate with methyl9-chloro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoate(Preparation 8, above), thereby yielding the desired formula-XXXVIItitle compound.

As shown in Chart D, the formula-XXXVII alkylated ketal is transformedvia the formula-XXXVIII glycol, thence the mesylate, to a PGE-typecompound. Concentrated hydrochloric acid (2.5 ml.) is added to asolution of the formula-XXXVII product above (about 2.0 g.) in a mixtureof 50 ml. of tetrahydofuran and 2.5 ml. of water. The mixture is stirredat 25° C. under nitrogen for 6 hrs. The resulting mixture is thenconcentrated under reduced pressure, and the residue is extracted withethyl acetate. The extract is washed with brine, dried, and concentratedtodl-methyl-9[endo-6-(1,2-dihydroxy-2-methylheptyl)-3-oxobicyclo[3.1.0.]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoate (formula-XXXVIII).Thereafter, following the procedure of Example 3, there is obtaineddl-15-methyl-3-oxa-3,5-inter-m-phenylene-4-nor-PGE₂ methyl ester.

Following the procedure of Example 9, but using formula-XLIII exoreactants in place of the endo reactant, there are obtained exo productsin each corresponding intermediate of Example 9.

With excess base (e.g., 26 g.) and a longer reaction time (e.g., 24 hrs.at 25° C.) during the alkylation step, the production of a substantialamount of the beta isomer is assured.

Following the procedures of Examples 9-d, but using thetrans-7-nonenoate of Preparation 9, above, instead of thecis-7-nonenoate, there is obtained the corresponding formula-XXXVIIalkylated ketal wherein the carboxy side chain is in trans configurationinstead of cis.

Also following the procedures of Example 9, but replacing theformula-XLIII olefin with each of the endo and exo forms of theformula-XLIII bicyclo olefins described in the paragraphs followingExample 1, there are obtained the corresponding alpha and beta, exo andendo, alkylated ketals within the scope of formula XXXVII.

Also following the procedures of Example 9-d, but replacing methyl9-chloro-3-oxa-3,7-inter-m-phenylene-4,5,6,-trinor-cis-7-nonenoate withthe formula-LV compounds of the paragraphs following Preparations 8 and9, viz. cis or trans methyl 9-bromo-3-oxa-4,7-inter-o-phenylene-5,6-dinor-7-nonenoate, methyl10-bromo-3-oxa-4,8-inter-m-phenylene-5,6,7-trinor-8-decenoate, andmethyl11-bromo-3-oxa-4,9-inter-p-phenylene-5,6,7,8-tetranor-9-undecenoate,there are obtained the corresponding formula-XXXVII compounds.Thereafter, these alkylated ketals are transformed following the stepsof Chart D as described in Example 9 to the corresponding PGE₂ typecompounds.

Also following the procedure of Example 9-d, but using in place of thenonenoate alkylating agent, methylm-(chloromethyl)phenoxyacetate(Preparation 2), ethylo-(bromoethyl)benzyloxyacetate (Preparation 3), methyl9-bromo-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate(Preparation 7), and methyl11-bromo-3-oxa-4,9-inter-p-phenylene-5,6,7,8-tetranor-9-undecyanoate(following Preparation 7), there are obtained alpha and beta, exo andendo, compounds corresponding to the product of Example 9 with##SPC124##

in place of the ##SPC125##

moiety of the Example-9 formula-XXXVII product. In the same manner, butusing formula LIII-to -LVI alkylating agents within the scope of theformula ##EQU69## there are obtained the corresponding formula-XXXVIIproducts.

Also following Example 9-d, other esters of the nonenoate alkylatingagent and of the other above-mentioned alkylating agents within thescope of R₁₀ as above-defined, e.g., the methyl, isopropyl, tert-butyl,octyl, β,β,β-trichloroethyl, cyclohexyl, benzyl, and phenyl esters,there are obtained the corresponding esters of these alpha and beta, exoand endo, formula-XXXVII bicyclo[3.1.0]hexane cyclic ketak alkylationproducts.

Also following the procedure of Example 9 but using in combination eachof the above-described alternative formula-XLIII bicyclo[3.1.0]hexaneolefin reactants (e.g. following Example 1) and each of theabove-described omega-halo alkylation reactants within the scope of##EQU70## (e.g. following Example 1) there are obtained formula-XXXVIIcompounds corresponding to the product of Example 9 but differenttherefrom with respect to both the carboxylate-terminated side chain andthe side chain attached to the cyclopropane ring of the product, and intheir respective alpha or beta and exo or endo configuration.

Following the procedure of Example 9 but using in place of the acetonideeach of the specific formula-XXXVII exo and endo, alpha and beta,saturated, cis and trans -phenyl-and acetylenic bicyclo[3.1.0]hexanecyclic ketal esters defined above, there are obtained the correspondingformula-XXXVIII dihydroxy compounds, and thence the corresponding PGEtype compounds.

EXAMPLE 10 dl-Methyl7-[Endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate(Formula-XLIV, Chart E; G is ##SPC126##

R₂, r₉, and R₂₆ are hydrogen; R₁₀ is methyl; Z' is ##SPC127##

and ˜ is endo and alpha).

Refer to Chart E. Following the procedures of Example 1-B, but replacingendo-6-(1-heptenyl)bicyclo[3.1.0]-hexan-3-one withendo-6-(cis-4-phenyl-1-butenyl)-bicyclo[3.1.0]hexan-3-one (Preparation4), and replacing methyl m-(chloromethyl)phenoxyacetate with methyl9-chloro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate(Preparation 7), there is obtained the title compound.

EXAMPLE 11 dl-Methyl 7-[Endo-6-(4-phenyl-1,2-dimesyloxy-butyl)-3-oxobicyclo[3.1.0.]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate(Formula-XLVI, Chart E; G' is ##SPC128##

R₂, r₉, and R₂₆ are hydrogen; R₁₀ and R₁₃ are methyl; Z' is ##SPC129##

and ˜ is alpha and endo).

a. There is first prepared the formula-XLV dihydroxy compound. Followingthe procedures of Example 2, but replacing dl-methyl7-[endo-6-(1-heptenyl)-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-heptanoatewith dl-methyl7-[endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl-]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate(Example 10), there are obtained isomers of the desired formula-XLVcompound, dl-methyl 7-[endo-6-(4-phenyl-1,2-dihydroxybutyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7nonynoate.

b. Following the procedures of Example 3, but replacing that formula-XLVdihydroxy heptanoate compound with the formula-XLV nonynoate compound ofA above, there is obtained the desired formula-LXVI dimesyloxy titlecompound.

EXAMPLE 12 dl-Methyl9-[Endo-6-(1,2-dihydroxy-4-phenyl-butyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-trans-7-nonenoateAcetonide (Formula-XXVII, Chart D: G is ##SPC130##

J' is trans ##SPC131##

R₂, R₉, and R₂₆ are hydrogen; R₁₀, R₁₁, and R₁₂ are methyl; and ˜ isendo and alpha)

Refer to the sequence of reactions from formula L to formula XXXVI, andto Chart D.

a. There is first prepared the formula-Ll dihydroxy compound. To asolution of the formula-XLIII olefin (Preparation 4, above,approximately 10.0 g.) in water is added a solution of potassiumchlorate (10.0 g.) and osmium tetroxide (0.65 g.) in 250 ml. of water.The mixture is stirred vigorously for 5 hrs. at 50° C. Then, the cooledmixture is concentrated under reduced pressure, the residue is extractedrepeatedly with dichloromethane, and the combined extracts are dried andconcentrated. The residue is chromatographed on about 1000 g. of silicagel, and eluted successively with 3 l of 10% ethyl acetate in a mixtureof isomeric hexanes (Skellysolve B), with 5 l. of 25% ethyl acetate inSkellysolve B, and then with 50% ethyl acetate in Skellysolve B,collecting 500 ml. eluate fractions. Fractions shown by TLC to containthe desired product are combined and evaporated to dryness to givedl-endo-6-(1,2-dihydroxy-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-one(formula-LI).

b. A solution of the product of step a above (about 8.0 g.) and 700 mg.of potassium bisulfate in 140 ml. of acetone is stirred at 25° C. for 64hrs. Then, sodium carbonate monohydrate (710 mg.) is added, and themixture is stirred 10 min. The acetone is concentrated at reducedpressure, and water is added. The aqueous solution is extractedrepeatedly with dichloromethane, and the extracts are combined, washedwith water, dried, and concentrated. The residue is chromatographed on400 g. of silica gel, being eluted with 2 l. of 10% ethyl acetate inSkellysolve B, and then with 4 l. of 15% ethyl acetae in Skellysolve B.The 15% ethyl acetate eluates are concentrated to the formula-XXXVIketal, dl-endo-6-(1,2-dihydroxy-4-phenylbutyl)-bicyclo[3.1.0]hexan-3-oneacetonide.

c. To prepare the formula-XXXVII compound, the ketal above is alkylatedfollowing the procedure of Example 1-B, but replacing methylm-(chloromethyl)phenoxyacetate with methyl9-chloro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-trans-7-nonenoate(Preparation 9, above), thereby yielding the title compound.

Following the procedures of Example 9, the formula-XXXVII compound istransformed via the formula-XXXVIII and -XXXIX compounds to thecorresponding formula-XL PGE-type compound.

EXAMPLE 139-[Endo-6-(1,2-dihydroxy-2-methylheptyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoicAcid Acetonide (Formula-LXXX, Chart G: G is n-pentyl; J' is ##SPC132##

R₉ and R₂₆ are hydrogen; R₂, R₁₁, and R₁₂ are methyl; and ˜ is alpha andendo.

Refer to Chart G. A solution of sodium borohydride (1.5 g.) in 10 ml. ofwater is added with stirring to a solution of formula-LXXVI dl-methyl9-[endo-6-(1,2-dihydroxy-2-methylheptyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoateacetonide (5.0 g.) in 110 ml. of absolute ethanol at 0° C. The mixtureis stirred for 2.5 hrs. at 0° to 5° C. Then, 40 ml. of acetone is added,and, after 5 min., the mixture is evaporated under reduced pressure. Theresidue is extracted with dichloromethane, and the extract is washedsuccessively with dilute hydrochloric acid and brine, dried, andconcentrated to the formula-LXXVII compound, dl-methyl9-[endo-6-(1,2-dihydroxy-2-methylheptyl)-3-hydroxybicyclo-[3.1.0]hex-2.alpha.-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoateacetonide.

This formula-LXXVII cyclic ketal hydroxy ester is dissolved in a mixtureof methanol (100 ml.) and 45% aqueous potassium hydroxide solution (30ml.), and the solution is stirred under nitrogen at 25° C. for 15 hrs.Two volumes of water are then added, and the mixture is acidified withcold hydrochloric acid and then extracted with a mixture ofdichloromethane and diethyl ether (1:3). The extract is washed withbrine, dried, and concentrated to the formula-LXXVIII compound,dl-9-[endo-6-(1,2-dihydroxy-2-methylheptyl)-3-hydroxybicyclo[3.1.0]hex-2.alpha.-yl]-thereare obtained the corresponding formula-LXXVII, LXXVIII, and LXXXcompounds.

EXAMPLE 14dl-7-[Endo-6-(1-heptenyl)-3-oxobicyclo[3.1.0]-hex-2α-yl]-3-oxa-4,7-inter-o-phenylene-5,6-dinor-heptanoicAcid (Formula-LXXXVI, Chart H: G is n-pentyl; Z' is ##SPC133##

R₂, r₉, and R₂₆ are hydrogen; and ˜ is alpha and endo).

Refer to Chart H. Following the procedure of Example 13, theformula-LXXXII compound, dl-ethyl7-[endo-6-(1-heptenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-4,7-intero-phenylene-5,6-dinor-heptanoateis reduced with sodium borohydride to the formula-LXXXIII compound,dl-ethyl7-[endo-6-(1-heptenyl)-3-hydroxybicyclo[3.1.0]hex-2α-yl]-3-oxa-4,7-inter-o-phenylene-5,6-dinor-heptanoate.That hydroxy ester is then saponified as described in Example 13 to theformula-LXXXIV compound,dl-7-[endo-6-(1-heptenyl)-3-hydroxybicyclo[3.1.0]hex-2α-yl]-3-oxa-4,7-intero-phenylene-5,6-dinor-heptanoicacid. That hydroxy acid is then oxidized as described in Example 13 tothe title compound.

Following the procedure of Example 14 but substituting for thatformula-LXXXII compound, the formula-LXXXII compound of Example 10, viz.dl-methyl7-[endo-6-(cis-4-phenyl-1-butenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7inter-m-phenylene-4,5,6-trinor-7-nonynoate,there is obtained on reduction the corresponding formula-LXXXIIIcompound, dl-methyl-7-[endo-6-(cis-4-phenyl-1-butenyl)-3-hydroxybicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate;there is likewise obtained on saponification the correspondingformula-LXXXIV compound,dl-7-[endo-6-(cis-4-phenyl-1-butenyl)-3-hydroxybicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoicacid; and there is likewise obtained on oxidation the correspondingformula-LXXXVI compound,dl-7-[endo-6-(cis-4-phenyl-1-butenyl)-3-oxabicyclo-[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoicacid.

Following the procedure of Example 14, but using in place of theformula-LXXXII 3-oxobicyclo[3.1.0]hexane ester, each of the specificformula-LXXXII endo and exo, alpha and beta, saturated and acetylenicesters described in and following the Examples 1, 6, and 10 is reducedwith sodium borohydride to give the corresponding formula-LXXXIII3-hydroxy-bicyclo[3.1.0]hexane ester. That hydroxy ester is thensaponified as described in Example 13 to the correspondingformula-LXXXIV 3-hydroxybicyclo-[3.1.0]hexane acid. That hydroxy acid isthen oxidized as described in Example 13 to the correspondingformula-LXXXVI 3-oxobicyclo[3.1.0]hexane acid.

EXAMPLE 15 dl-15-Dehydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub.α Methyl Ester (Formula-XCI, Chart J: E' is trans --CH=CH--, G isn-pentyl, J' is ##SPC134##

R₁ is methyl, R₂₆ is hydrogen, and ˜ is alpha).

Refer to Chart J. A solution ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α methyl ester(Example 4, about 0.5 g.) in 24 ml. of dioxane is stirred at 50° C.under nitrogen and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.37 g.)is added. The mixture is stirred at 50° C. for 24 hrs., cooled to roomtemperature, and filtered. The filter cake is washed withtetrahydrofuran, and the filtrate and wash are combined and concentratedunder reduced pressure. The residue is taken up in dichloromethane andwashed with brine, then dried over sodium sulfate and concentrated underreduced pressure. The residue is chromatographed over 90 g. of silicagel wet-packed in 8% ethanol in dichloromethane, eluting with 300 ml. of2%, 300 ml. of 3%, 225 ml. of 7.5% and 245 ml. of 10% ethanol indichloromethane, taking 15-ml. fractions. Fractions shown by TLC tocontain the desired product are combined and concentrated to the titlecompound.

EXAMPLE 16 dl-15-Methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub.α Methyl Ester (Formula-XX: C_(g) H_(2g) g and C_(p) H_(2p) arevalence bonds in meta relationship, G is n-pentyl, Q is ##EQU71## R₁ ismethyl, and ˜ is alpha).

Refer to Chart J. A solution of 0.413 g. ofdl-15-dehydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.αmethyl ester (Example 15, about 0.4 g.), hexamethyldisilazane (3 ml.)and trimethylchlorosilane (0.5 ml.) in 20 ml. of tetrahydrofuran isallowed to stand at about 25° C. for 20 hrs. The mixture is filtered andthe filtrate is concentrated under reduced pressure. Xylene (10 ml.) isadded to the residue and removed by concentration under reducedpressure. The residue is dissolved in anhydrous ether and 110% of thetheoretical amount of 3 M methyl magnesium bromide in ether is added.The mixture is allowed to stand 20 min. at about 25° C. and poured into100 ml. of saturated aqueous ammonium chloride. The ether layer isseparated, the aqueous layer is extracted with ether, and the etherextracts are combined and washed with brine, dried over sodium sulfate,and concentrated under reduced pressure. The residue is dissolved in 300ml. of ethanol and 30 ml. of water containing 3 drops of glacial aceticacid, and the mixture is stirred for 2 hrs. at about 25° C. The mixtureis concentrated under reduced pressure to an aqueous residue and theresidue is extracted with dichloromethane. The dichloromethane extractis concentrated under reduced pressure to give a residue which ischromatographed over 60 g. of silica gel wet-packed in 8% ethanol indichloromethane, eluting with 200 ml. of 5% and 800 ml. of 10% ethanolin dichloromethane and taking 10-ml. fractions. Fractions shown by TLCto contain the desired product are combined and concentrated to yieldthe title compound. Other fractions yield the 15-epimer.

Likewise, using the corresponding3-oxa-4,7-inter-o-phenylene-5,6-dinor-PGF₁ .sub.α or PGF₁ .sub.βcompound instead of the above oxa-phenylene compounds, there areobtained the corresponding 15-dehydro PGF₁ .sub.α or PGF₁ .sub.β-typecompounds, and finally thedl-15-methyl-3-oxa-4,7-inter-o-phenylene-5,6-dinor-PGF₁ .sub.α or -PGF₁.sub.β ethyl esters and their 15-epimers.

EXAMPLE 17dl-13,14-Dihydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ MethylEster (Formula XIX C_(g) H_(2g) and C_(p) H_(2p) are valence bonds inmeta relationship, G is n-pentyl, Q is ##EQU72## R₁ is methyl, and ˜ isalpha).

Refer to Chart B. A solution ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ methyl ester (Example3, 100 mg.) in 10 mg. of ethyl acetate is shaken with hydrogen at aboutone atmosphere pressure at 25° C. in the presence of 5% rhodium oncharcoal (15 mg.). After approximately one equivalent of hydrogen isabsorbed, the hydrogenation is stopped, and the catalyst is removed byfiltration. The filtrate is concentrated, aand the residue ischromatographed on 25 g. of silica gel, eluting with 50-100% ethylacetate gradient in Skellysolve B. Those fractions shown by TLC tocontain the desired product free of the starting product andhydrogenolysis products are combined and concentrated to the titlecompound.

Following the procedure of Example 17,dl-3-oxa-3,7-m-phenylene-4,5,6-trinor-PGE₁ methyl ester is reduced todl-13,14-dihydro-3-oxa-3,7-m-phenylene-4,5,6-trinor-PGE₁ ethyl ester.Likewise, dl-3-oxa-4,7-o-phenylene-5,6-dinor-PGE₁ methyl ester isreduced to dl-13,14-dihydro-3-oxa-4,7-o-phenylene-5,6-dinor-PGE₁ methylester.

Also following the procedure of Example 17,dl-3-oxa-3,7-m-phenylene-4,5,6-trinor-PGE₂, -trans-5,6-dehydro-PGE₁, and-5,6-dehydro-PGE₂ are each reduced todl-13,14-dihydro-3-oxa-3,7-m-phenylene-4,5,6-trinor-PGE₁, using twoequivalents of hydrogen for the first two reactions, and threeequivalents of hydrogen for the third. Likewise, the correspondingdl-3-oxa-4,7-o-phenylene-5,6-dinor- compounds are reduced todl-13,-14,-dihydro-3-oxa-4,7-o-phenylene-5,6-dinor-PGE₁.

Also following the procedure of Example 17, the ethyl ester and the freeacid form of the formula XVI-to -XVIII PGE compounds in their variousspatial configurations are transformed to the corresponding13,14-dihydro PGE₁ compound by catalytic hydrogenation, usingequivalents of hydrogen appropriate to the degree of unsaturation of thereactant, i.e., one equivalent for the PGE₁ type, two equivalents forthe PGE₂ type and trans-5,6-dehydro-PGE₁ type, and three equivalents forthe 5,6-dehydro-PGE₂ type.

Also following the procedure of Example 17,dl-3-oxa-3,7-m-phenylene-4,5,6-trinor-PGF₁ .sub.α and its ethyl esterare reduced to dl--13,14-dihydro-3-oxa-3,7-m-phenylene-4,5,6-PGF₁ .sub.αand its ethyl ester, respectively.

Also following the procedure of Example 17, the ethyl ester and the freeacid form of the formula-XX to -XXII PGF compounds in their variousspatial configurations are transformed to the corresponding13,14-dihydro PGF₁ 301 or PGF₁ .sub.β compound by catalytichydrogenation, using equivalents of hydrogen appropriate to the degreeof unsaturation of the reactant.

EXAMPLE 18dl-13,14-Dihydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁(Formula-XXVII: C_(g) H_(2g) and C_(p) H_(2p) are valence bonds in metarelationship, G is n-pentyl, Q is ##EQU73## R₁ is hydrogen, and ˜ isalpha).

Refer to Chart B. A suspension of disodium azodiformate (50 mg.) in 5ml. of absolute ethanol is added to a stirred solution of3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ (Example 5, 50 mg.) in 10ml. of absolute ethanol under nitrogen at 25° C. The mixture is madeacid with glacial acetic acid, and then is stirred under nitrogen at 25°C. for 8 hrs. The resulting mixture is concentrated under reducedpressure, and the residue is mixed with a mixture of diethyl ether andwater (1:1). The diethyl ether layer is separated, dried, andconcentrated to the title product.

following the procedure of Example 18,dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ methyl ester is reducedto dl-13,14-dihydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ methylester.

Also following the procedure of Example 18,dl-3-oxa3,7-inter-m-phenylene-PGA₂, -trans-5,6-dehydro-PGA₁, and5,6-dehydro-PGA₂ are each reduced todl-13,14-dihydro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁, usingamounts of the disodium azodiformate reactant appropriate to the degreeof unsaturation of the reactant.

Also following the procedure of Example 18, the methyl ester and thefree acid form of the formula-XVI to -XVIII PGE type compounds, theformula-XX to -XXII PGF type compounds, the formula-XXIV to -XXVI PGAtype compounds, and the formula-XXVIII to -XXX PGB type compounds aretransformed to the corresponding 13,14-dihydro PGE₁, PGF₁, PGA₁, or PGB₁type compound by diimide reduction, using amounts of disodiumazodiformate reactant appropriate to the degree of unsaturation of thePGE, PGF, PGA, or PGB type reactant.

EXAMPLE 19 dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ Methyl Ester(Formula-XXIV: C_(g) H_(2g) and C_(p) H_(2p) are valence bonds in metarelationship, G is n-pentyl, Q is ##EQU74## R₁ is methyl, and ˜ isalpha).

Refer to Chart D. A solution of the formula-XXXIX bismesylate, dl-methyl7-[endo-6-(1,2-dimesyloxyheptyl)-3-oxabicyclo[3.1.0]hex-2α-yl]-3-oxa-3,7-inter-m-phenylene4,5,6-trinor-heptanoate(Example 3, about 10 g.) in 75 ml. -inter-m-phenylene- of acetone ismixed with 10 ml. of water and 20 ml. of saturated aqueous sodiumbicarbonate solution. The mixture is refluxed under nitrogen for 4 hrs.Then, the mixture is cooled, acidified with 5% hydrochloric acid, andextracted with ethyl acetate. The extract is washed with brine, dried,and concentrated to give the title product.

Following the procedure of Example 19, each of the bismesylates definedin Example 3 is transformed to the corresponding PGA-type ester,including the β,β,β-trichloroethyl esters. Thereafter, each of theβ,β,β-trichloroethyl esters is transformed to the corresponding PGA-typefree acid by the procedure of Example 23, below.

EXAMPLE 20 dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGB₁(Formula-XXVIII: C_(g) H_(2g) and C_(p) H_(2p) are valence bonds in metarelationship, G is n-pentyl, Q is ##EQU75## R₁ is hydrogen, and ˜ isalpha).

Refer to Chart A. A solution ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ (200 mg.) in 100 ml. of50% aqueous ethanol containing about one gram of potassium hydroxide iskept at 25° C. for 10 hrs. under nitrogen. Then, the solution is cooledto 10° C. and neutralized by addition of 3 N. hydrochloric acid at 10°C. The resulting solution extracted repeatedly with ethyl acetate, andthe combined ethyl acetate extracts are washed with water and then withbrine, dried, and concentrated to give the title compound.

Following the procedure of Example 20,dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ is also transformed tothe PGB₁ -type title compound.

Following the procedure of Example 20, each of the formula XVI-to -XIXPGE compounds and formula XXIV-to -XXVII PGA compounds are transformedto the corresponding PGB compounds.

EXAMPLE 21 dl-15-Methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁Methyl Ester (Formula XVI: C_(g) H_(2g) and C_(p) H_(2p) are valencebonds in meta relationship, G is n-pentyl; Q is ##EQU76## R₁ is methyl,and ˜ is alpha).

Refer to Chart I. A solution ofdl-15-methyl-3-oxa3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α methylester (95 mg.) in 40 ml. of acetone is cooled to -10° C. To it is added110% of the theoretical amount of Jones reagent (in the proportions of21 g. of chromic anhydride, 60 ml. of water, and 17 ml. of concentratedsulfuric acid), precooled to 0° C., with vigorous stirring. After about10 min., isopropyl alcohol (1 ml.) is added to the cold reactionmixture. After 5 min., the mixture is filtered and the filtrate isconcentrated at reduced pressure, and the residue is mixed with 5 ml. ofbrine. The mixture is extracted repeatedly with ethyl acetate, and thecombined extracts are washed with brine, dried with anhydrous sodiumsulfate, and concentrated at reduced pressure. The residue ischromatographed on 20 g. of neutral silica gel, eluting with 50% ethylacetate in Skellysolve B. Concentration of the eluates gives the titleproduct.

Following the procedure of Example 21, there is substituted for thedl-15-methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α methylester, the free acid, the propyl ester, the octyl ester, the cyclopentylester, the benzyl ester, the phenyl ester, the 2,4-dichlorophenyl ester,the 2-tolyl ester, of the β,β,β-trichloroethyl ester, there is obtainedthe correspondingdl-15-methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ compound.

Following the procedure of Example 21, but substituting for the15-methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α methylester, the methyl ester of each of the15-methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.β, -PGF₂.sub.α, -PGF₂ .sub.β, -5,6-dehydro-PGF₂ .sub.α, -5,6-dehydro-PGF₂.sub.β, -dihydro-PGF₁ .sub.α, and -dihydro-PGF₁ .sub.β compounds intheir various natural or 15-epi configurations and optical isomers istransformed to the corresponding PGE-type compound.

Following the procedure of Example 21, each of the various15-alkyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α methylester compounds, including the 15-ethyl, 15 propyl, 15-butyl, and15-substituted isomeric forms of propyl and butyl, is transformed to thecorresponding PGE type compound.

Also following the procedure of Example 21, each of the 15-alkylPGF-type acids and esters within the scope of formula-LXXXVIII (Chart I)is transferred to a 15-alkyl PGE-type acid or ester encompassed byformula-LXXXIX.

EXAMPLE 22 dl-15-Methyl-3-oxa-4,7-inter-o-phenylene-5,6dinor-PGA₁ MethylEster (Formula XXIV: C_(g) H_(2g) is a valence bond, C_(p) H_(2p) ismethylene, C_(g) H_(2g) and C_(p) H_(2p) are in ortho relationship, G isn-pentyl, Q is ##EQU77## R₁ is methyl, and ˜ is alpha).

Refer to Chart K. A mixture of the formula-XCV15-methyl-3-oxa-4,7-inter-o-phenylene-5,6-dinor-PGE₁ methyl ester(Example 21, 6 mg.), dicyclohexylcarbodiimide (20 mg.), copper (II)chloride dihydrate (2 mg.), and diethyl ether (2 ml.) is stirred undernitrogen at 25° C. for 16 hrs. Then, additional dicyclohexylcarbodiimide(20 mg.) is added, and the mixture is stirred an additional 32 hrs. at25° C. under nitrogen. The resulting mixture is filtered, and thefiltrate is concentrated under reduced pressure. The residue ischromatographed by preparative thin layer chromatography with the A-IXsystem to give the title compound.

Following the procedure of Example 22, but substituting for theoxa-phenylene PGE₁ compound, the methyl esters ofdl-15-methyl-3-oxa-4,7-inter-o-phenylene-5,6-dinor-PGE₂,-5,6-dehydro-PGE₂, and -dihydro-PGE₁, there are obtained thecorresponding formula-XCVI compounds, viz., the methyl esters ofdl-15-methyl 3-oxa-4,7-inter-o-phenylene-5,6-dinor-PGA₂,-5,6-dehydro-PGA₂, and -dihydro-PGA₁.

Also following the procedure of Example 22, but substituting for thephenyl-substituted PGE₁ compound, the methyl esters ofdl-15-methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁, -PGE₂,-5,6-dehydro-PGE₂, and -dihydro-PGE₁, there are obtained thecorresponding formula-XCVI compounds, viz., the methyl esters ofdl-15-methyl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁, -PGA₂,-5,6-dehydro-PGA₂, and -dihydro-PGA₁.

Also following the procedure of Example 22, each of the formula-XCV(Chart K) compounds defined above in Example 21 is transformed to thecorresponding formula-XCVI compound.

EXAMPLE 23 dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ (FormulaXVI: C_(g) H_(2q) and C_(p) H_(2p) are valence bonds in metalrelationship, G is n-pentyl, Q is ##EQU78## R₁ is hydrogen, and ˜ isalpha).

Zinc dust (420 mg.) is added to a solution containingdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ β,β,β-trichloroethylester (100 mg.) in 5 ml. of a mixture of acetic acid and water (9:1v/v). This mixture is stirred under nitrogen 2 hrs. at 25° C. Ethylacetate (4 volumes) is then added, followed by addition of 1 N.hydrochloric acid (one volume). The ethyl acetate later is separated,washed with water and then with brine, dried, and evaporated. Theresidue is chromatographed on 15 g. of acidwashed silica gel (SilicarCC4), being eluted with 100 ml. of 50%, 100 ml. of 80%, and 200 ml. of100% ethyl acetate in Skellysolve B, collecting 20-ml. fractions. Thefractions containing the desired product and no starting material ordehydration products as shown by TLC are combined and concentrated tothe title compound.

Following the procedure of Example 23, each of the β,β,β-tribromoethyl,-triiodoethyl, β,β-dibromoethyl, -diiodoethyl, and the β-iodoethylesters of dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ is convertedto the free acid of dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ byreaction with zinc dust and acetic acid.

Following the procedure of Example 23, the β,β,βtrichloroethyl ester ofdl-15-methyl-3-oxa-3,5-inter-m-phenylene-4-nor-PGE₂ following Example 9above is converted to the respective free acid compound using zinc dustwith either propionic, butyric, pentanoic, or hexanoic acid instead ofacetic acid.

Following the procedure of Example 23, the β,β,β-trichloroethyl ester ofeach of the PGE, PGF, PGA, and PGF type compounds represented byformulas XVI-XXXV in their various structural configurations and opticalisomers is treated with zinc dust and acetic acid to obtain thecorresponding free acid form of the compound. The esters are prepared bythe procedures disclosed herein, using as intermediates formula-XXXVIIcyclic ketals or formula-XLIV or -LXX olefins wherein R₁₀ is haloethyl,e.g., β,β,β-trichloroethyl. These intermediates are prepared either byalkylation of the respective formula-XXXVI cyclic ketal (Chart D) orformula-XLIII or -LXIX olefin (Charts E and F) with the appropriatealkylating agent wherein R₁₀ is haloethyl, or by the transformation ofthe alkylated cyclic ketal or olefin by the steps shown in Charts G andH using procedures disclosed herein, yielding intermediates LXXIX,LXXXI, LXXXV, or LXXXVII.

EXAMPLE 24

dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α and -PGF₁ .sub.β(Formula XX; C_(g) H_(2g) and C_(p) H_(2p) are valence bonds in metarelationship, G is n-pentyl, Q is ##EQU79## R₁ is hydrogen, and ˜ isalpha or beta).

A solution of 146 mg. ofdl-3-oxo-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α ethyl ester in amixture of 4.5 ml. of methanol and 1.5 ml. of water is cooled to 5° C.and 0.6 ml. of 45% aqueous potassium hydroxide is added. The mixture isallowed to stand 3.5 hrs. at 25° C., then is diluted with 75 ml. ofwater and extracted once with ethyl acetate to remove any neutralmaterial. The aqueous layer is separated, made acid with dilutehydrochloric acid and extracted 4 times with ethyl acetate. The extractsare combined and washed 3 times with water, once with brine, dried oversodium sulfate, and concentrated to give the PGF₁.sub.α -type titlecompound.

Following the procedure of Example 24, the methyl ester ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinorPGF₁.sub.β is transformed tothe free acid, i.e. the formula-XX PGF₁.sub.β -type title compound.

Following the procedure of Example 24, the methyl or ethyl esters of thevarious oxa-phenylene PGF-type compounds and their isomers aretransformed to the corresponding free-acid oxa-phenylene PGF-typecompounds.

EXAMPLE 25 dl-3-Oxa-3,5-inter-m-phenylene-4-nor-PGF₂.sub.α Methyl Ester(Formula XXI: C_(j) H_(2j) and C_(p) H_(2p) are valence bonds in metarelationship, G is n-pentyl, Q is ##EQU80## R₁ is methyl, R₃ and R₄ arehydrogen, and ˜ is alpha).

Refer to Chart C.dl-5,6-Dehydro-3-oxa-3,5-inter-m-phenylene-4-nor-PGF₂.sub.α methyl ester(200 mg.) in pyridine (4 ml.) and methanol (10 ml.) is hydrogenated inthe presence of a 5%-palladium-on-barium sulfate catalyst (200 mg.) at25° and atmospheric pressure. The reaction is terminated when slightlymore than one equivalent of hydrogen is absorbed. The mixture isfiltered and evaporated. Ethyl acetate is added and residual pyridine isremoved by addition of ice and 3 N. hydrochloric acid. The ethyl acetatelayer is washed with 1 N. hydrochloric acid and then with brine, dried,and concentrated to yield the title product.

Following the procedure of Example 25, the 5,6-dehydro oxa-phenylenePGF₂ compounds following Example 4 are reduced to the corresponding PGF₂compounds. Likewise, the 5,6-dehydro oxa-phenylene PGE, PGA, and PGBcompounds disclosed herein are reduced to the corresponding PGE₂, PGA₂,and PGB₂ compounds.

EXAMPLE 26

dl-β,β,β-Trichloroethyl9-[endo-6-(1,2-dihydroxy-2-methylheptyl)-3-hydroxybicyclo[3.1.0]-hex-2.alpha.-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6trinor-cis-7-nonenoateAcetonide (Formula LXXIX, Chart G: G is n-pentyl, J' is cis ##SPC135##

haloethyl is β,β,β-trichloroethyl, R₂, R₁₁, and R₁₂ are methyl, R₉ andR₂₆ are hydrogen, and ˜ is alpha and endo).

Refer to chart G. Successively, β,β,β-trichloroethanol (25 ml.),pyridine (15 ml.), and dicyclohexylcarbodiimide (4.0 g.) are added to asolution of formula-LXXVIII compounddl-9-[endo-6-(1,2-dihydroxy-2-methylheptyl)-3-hydroxybicyclo[3.1.0]hex-2.alpha.-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-cis-7-nonenoicacid acetonide (Example 13, 2.0 g.) in 100 ml. of dichloromethane. Thismixture is stirred 3 hrs. under nitrogen at 25° C. Water (50 ml.) isthen added, and the mixture is stirred 10 min. The dichloromethane isconcentrated under reduced pressure, and the residue is extractedrepeatedly with ethyl acetate. The combined extracts are washed withice-cold 3 N. hydrochloric acid. Then, the extracts are washedsuccessively with aqueous sodium bicarbonate solution and brine, dried,and concentrated under reduced pressure. The residue is chromatographedon 600 g. of silica gel, eluting with 10 l. of a 20-100% ethylacetate-Skellysolve B gradient, collecting 50ml. fractions. The middlefractions which show a product free of starting materials on TLC arecombined and concentrated under reduced pressure to give the titlecompound.

Following the procedure of Example 26, but using in place of theformula-LXXVIII 3-hydroxybicyclo[3.1.0]hexane acid acetonide, each ofthe specific endo and exo, alpha and beta, saturated and unsaturatedformula-LXXVIII hydroxy acid ketals defined after Example 13, there areobtained the corresponding β,β,β-trichloroethyl esters of those3-hydroxybicyclo[3.1.0]hexane acids.

Following the procedure of Example 26, but using in place of theformula-LXXVIII 3-hydroxybicyclo[3.1.0]hexane acid ketal, each of thespecific formula-LXXX 3-oxo-acid ketals defined after Example 13, thereare obtained the corresponding formula-LXXXI β,β,β-trichloroethyl estersof those 3-oxo-acid ketals.

Following the procedure of Example 26 but using in place of theformula-LXXVIII 3-hydroxy-acid ketal, each of the specificformula-LXXXIV (Chart H) 3-hydroxy and formula-LXXXVI 3-oxo acidsdefined after Example 14, there are obtained the correspondingformula-LXXXV and formulaLXXXVII β,β,β-trichloroethyl esters of thoseacids, respectively.

Following the procedures of Examples 3 and 9, each of the formula-LXXXIcyclic ketal haloethyl esters of Example 26 is transformed to thecorresponding formula-XL (Chart D) 3-oxa or 4-oxa phenyl-substitutedPGE₁ β,β,β-trichloroethyl ester. Thence, following the procedure ofExample 23, each of the esters is transformed to the oxaphenylene PGE₁acid compound wherein R₁₀ of formula-XL is replaced with hydrogen.

Following the procedure of Examples 2 and 3 each of the formula-LXXXVIIolefin haloethyl esters of Example 26 is transformed to thecorresponding formula-XLVII (Chart E) oxa-phenylene PGE₁β,β,β-trichloroethyl ester. Thence, following the procedure of Example23, each of the esters is transformed to the corresponding PGE₁ -typeacid compound wherein R₁₀ of formula-XL is replaced with hydrogen.

EXAMPLE 27 dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ Methyl Ester(Formula XXIV: C_(g) H_(2g) and C_(p) H_(2p) are valence bonds in metarelationship, G is n-pentyl, Q is ##EQU81## R₁ is methyl, and ˜ isalpha).

A solution of diazomethane (about 50% excess) in diethyl ether (25 ml.)is added to a solution ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-pGA₁ (Example 5, 50 mg.) in25 ml. of a mixture of methanol and diethyl ether (1:1). The mixture isallowed to stand at 25° C. for 5 min. Then the mixture is concentratedto give the title compound.

Following the procedure of Example 27, each of the other specificphenyl-substituted PGB type, PGA type, PGE type, and PGF type free acidsdefined above is converted to the corresponding methyl ester.

Also following the procedure of Example 27, but using in place of thediazomethane, diazoethane, diazobutane, 1-diazo-2-ethylhexane, anddiazocyclohexane, there are obtained the corresponding ethyl, butyl,2-ethylhexyl, and cyclohexyl esters of3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁. In the same manner, eachof the other specific phenyl-substituted PGB type, PGA type, PGE type,and PGF type free acids defined above is converted to the correspondingethyl, butyl, 2-ethylhexyl, and cyclohexyl esters.

EXAMPLE 28 dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ Methyl EsterDiacetate. ,

Acetic anhydride (5 ml.) and pyridine (5 ml.) are mixed withdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ methyl ester (Example3, 20 mg.), and the mixture is allowed to stand at 25° C. for 18 hrs.The mixture is then cooled to 0° C., diluted with 50 ml. of water, andacidified with 5% hydrochloric acid to pH 1. That mixture is extractedwith ethyl acetate. The extract is washed successively with 5%hydrochloric acid, 5% aqueous sodium bicarbonate solution, water, andbrine, dried and concentrated to give the title compound.

Following the procedure of Example 28 but replacing the acetic anhydridewith propionic anhydride, isobutyric anhydride, and hexanoic acidanhydride, there are obtained the corresponding dipropionate,diisobutyrate and dihexanoate derivatives ofdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ methyl ester.

Also following the procedure of Example 28, but replacing the3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ compound withdl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁ .sub.α and -PGF₁.sub.β,anddl-15-methyl-3-oxa13,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub..alpha.and -PGF₁ .sub.β, there are obtained the corresponding triacetatederivatives of the 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGFcompounds.

Also following the procedure of Example 28, each of thephenyl-substituted PGE type, PGF type, PGA type, and PGB type esters andfree acids defined above is transformed to the corresponding acetates,propionates, isobutyrates, and hexanoates, the PGE-type derivativesbeing dicarboxyacylates, the PGF-type derivatives beingtricarboxyacylates, and the PGA-type and PGB-type derivatives beingmonocarboxyacylates.

EXAMPLE 29 dl-3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ Sodium Salt.

A solution of dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ (Example23, 100 mg.) in 50 ml. of a water-ethanol mixture (1:1) is cooled to 5°C. and neutralized with an equivalent amount of 0.1 N, aqueous sodiumhydroxide solution. The neutral solution is concentrated to give thetitle compound.

Following the procedure of Example 29 but using potassium hydroxide,calcium hydroxide, tetramethylammonium hydroxide, andbenzyltrimethylammonium hydroxide in place of sodium hydroxide, thereare obtained the corresponding salts of dl-3-oxa-3,7l-inter-m-phenylene-4,5,6-trinor-PGE₁.

Also following the procedure of Example 29 each of thephenyl-substituted PGE type, PGF type, PGA type, and PGB type acidsdefined above is transformed to the sodium, potassium, calcium,tetramethylammonium, and benzyltrimethylammonium salts.

The various Preparations and Examples given above describe thepreparation of racemic intermediates and final products. Each of theintermediates and final products named and defined above is alsoobtained in each of the enantiomeric forms, d and l, by resolution thatcompound or by resolution of an intermediate used to prepare thatcompound. For example, natural configuration3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ free acid is prepared byresolution of dl-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGA₁ free acid(Example 5) or by dehydration as in Example 5 of optically active3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁ free acid with the sameabsolute configuration. These resolutions are carried out by proceduresknown in the art, and may be used to obtain prostaglandin-like materialshaving the spatial configuration of the natural prostaglandins, astypified by the following Examples 30-32.

EXAMPLE 30

Natural Configuration 3-oxa-3,5-inter-m-phenylene-4-nor-PGE₂ and PGF₂.sub.α Methyl Esters (Formula-XVII and -XXI: wherein C_(j) H_(2j) andC_(p) H_(2p) following the valence bonds in meta relationship, G isn-pentyl, Q is ##EQU82## R₁ is methyl; R₃ and R₄ are hydrogen; and ˜ isalpha).

The process shown in Chart D is used to prepare the PGE₂ -type compoundfirst. formula-XXXVIII formula-XXXVII cyclic ketal intermediate whereinformula-XVII is n-pentyl; J' is ##SPC136## PFG.sub. -Oxa-

R₂, r₉, and R₂₆ are hydrogen; R₁₀, R₁₁, and R₁₂ are methyl; and ˜ isendo and alpha is prepared following the procedures of Example 9.

The formula-XXXVII compound is resolved as its optical isomers by themethod of Corey et al., J. Am. Chem. Soc. 84, 2938 (1962), by reactingthis keto compound with optically active L(+)-2,3-butanedithiol in thepresence of p-toluene-sulfonic acid. The diastereomeric ketals arecompletely resolved on a preparative chromatographic column, and arethen hydrolyzed separately, following the procedure of Example 9, to theformula-XXXVII dihydroxy compounds. Transformation to the formula-XVIIPGE₂ -type compounds is accomplished by the procedures of Example 3. Ofthe separate diastereoisomers, one corresponds to the configuration ofnatural PGE₂ and the other to its enantiomer. Conversion of the PGE₂-type compound having the configuration of the natural product to thePGF₂.sub.α -type methyl ester is done by borohydride reduction followingthe procedure of Example 4. The natural configuration-PGF₂.sub.α -typefree acid is formed from the methyl ester by saponification, followingthe procedure of Example 24.

EXAMPLE 31 Natural Configuration 3-oxa-3,5-inter-o-phenylene-4-nor-PGE₁Methyl Ester (Formula XVI: C_(g) H_(2g) is ethylene; C_(p) H_(2p) is avalence bond in ortho relationship to C_(g) H_(2g), G is n-pentyl, Q is##EQU83## R₁ is methyl, and ˜ is alpha).

to Chart E. A. Methyl7-[endo-6-(1-heptenyl)-3-oxobicyclo-[3.1.0]hex-2α-yl]-3-oxa-3,5-inter-o-phenylene-4-nor-heptanoate(Formula-XLIV, Chart E: G is n-pentyl; R₂, R₉, and R₂₆ are hydrogen; R₁₀is methyl; Z' is ##SPC137##

and ˜ is alpha and endo).

1. Methyl 2-(3-hydroxypropyl)phenoxyacetate. To a solution of potassiumt-butoxide (11.2 g.) in 150 ml. of dry tetrahydrofuran at 0°-5° C. isadded with stirring 3-(o-hydroxyphenyl)propanol (15.2 g.) followed in afew minutes by methyl bromoacetate (20 g.). The cooling bath is removedand the mixture is stirred at ambient temperature until the reactionmixture becomes essentially neutral. The mixture is concentrated invacuo at 30° C. and the residue is shaken with ether and water. Theorganic layer is washed with dilute potassium hydroxide solution, water,brine, and is dried over sodium sulfate and then concentrated in vacuo.The residue is distilled in a high vacuum to afford methyl2-(3-hydroxypropyl)phenoxyacetate. 2. Methyl2-(3-chloropropyl)phenoxyacetate. A mixture of methyl2-(3-hydroxypropyl)phenoxyacetate (step A-1, 25 g.) and thionyl chloride(20 ml.) is heated to reflux for 1-2 hrs. The excess thionyl chloride isremoved in vacuo and the residue is distilled in a high vacuum to affordmethyl 2-(3-chloropropyl)phenoxyacetate. 3. Methyl2-(3-iodopropyl)phenoxyacetate. A mixture of methyl2-(3-chloropropyl)phenoxyacetate (step A-2, 24.3 g.), acetone (250 ml.)and sodium iodide (30 g.) is heated to reflux with stirring for about 40hrs. The mixture is cooled, filtered and the filtrate is concentrated invacuo at about 30° C. The residue is diluted with ether and the solutionis washed with water, dilute sodium thiosulfate solution, brine and isdried over magnesium sulfate and then concentrated in vacuo. Theproduct, methyl 2-(3-iodopropyl)phenoxyacetate, is used directly in thenext step. 4. Following the procedure of Example 1-B, but replacing themethyl m-(chloromethyl)phenoxyacetate with methyl 2-(3-iodopropyl)phenoxyacetate (step A-3, 18 g.) and allowing the alkylation reaction toproceed for about 5 min. before acidification with hydrochloric acid,there is obtained the desired formula-XLIV methyl7-]endo-6-(1-heptenyl)-3-oxobicyclo[3.1.0]hex-2α-yl]-3-oxa-3,5-inter-o-phenylene-4-nor-heptanoate.

Following the procedure of Example 30, the above racemic formula-XLIVcompound is resolved as two optically active isomers. These are bothtransformed by the subsequent steps of this example to the formula-XVIPGE₁ -type compounds, one of which corresponds to the configuration ofnatural PGE₁ and the other to its enantiomer.

B. Methyl7-[endo-6-(1,2-dihydroxyheptyl)-3-oxo-bicyclo[3.1.0]hex-2α-yl]-3-oxa-3,5-inter-o-phenylene-4-nor-heptanoate(Formula-XLV, Chart E: G' is n-pentyl; R₂, R₉, and R₂₆ are hydrogen; R₁₀is methyl; Z' is ##SPC138##

and ˜ is alpha and endo). To a solution of methyl7-[endo-6-(1-heptenyl)-3-oxobicyclo[3.1.0]-hex-2α-yl]-3-oxa-3,5-inter-o-phenylene-4-nor-heptanoate(step A, above, 1.8 g.) in 30 ml. of tetrahydrofuran at 50° is added,with stirring, osmium tetroxide (200 mg.) followed by potassium chlorate(1.2g.) and 15 ml. of water. The reaction mixture is maintained at 50°for 2 hrs., cooled, the tetrahydrofuran is removed, and the aqueousphase is extracted with dichloromethane. The organic layer is dried andconcentrated and the residue is chromatographed on 200 g. of silica gel.The column is eluted with 1 l. of 35% ethyl acetate-benzene and 1 l. of40% ethyl acetate-benzene, collecting 30-ml. fractions. Those fractionscontaining the formula-XLV compound, in its isomeric erythro and threoforms free of starting material and impurities, are combined andconcentrated.

C. Title compound. To a solution of the formula-XLV dihydroxy compound(step B, above, 0.8 g.) in 10 ml. of pyridine, cooled to 0°, is added1.2 ml. of methane-sulfonyl chloride. The reaction mixture is stirredfor 2 hrs. and 20 g. of ice is added. The mixture is extracted withether-dichloromethane (1:1) and the organic layer is washed successivelywith dilute hydrochloride acid, water, saturated aqueous sodiumbicarbonate, and brine, dried, and concentrated. The residue, containingthe bismesylate, is treated with 15 ml. of acetone and 10 ml. of waterand stirred for 8-16 hrs. at 25°. The acetone is removed in vacuo andthe remaining solution is extracted with dichloromethane. The extract isdried and concentrated and the residue is chromatographed on 150 g. ofsilica gel using 500 ml. ethyl acetate followed by 3% methanol ethylacetate as eluting solvent while collecting 30-ml. fractions. Thosefractions containing the formula-XLVII product, free of startingmaterial and impurities, are combined and concentrated to give the titlecompound; principle NMR spectral peaks at 6.57-7.3 (multiplet);5.42-5.65 (multiplet); 4.60 (singlet) and 3.76 (singlet) δ.

EXAMPLE 32 Natural Configuration3-Oxa-3,5-inter-o-phenylene-4-nor-PGF₁.sub.α Methyl Ester (Formula-XX:C_(g) H_(2g) is ethylene, C_(p) H_(2p) is a valence bond in orthorelationship to C_(g) H_(2g), G is n-pentyl, Q is ##EQU84## R₁ ismethyl, and ˜ is alpha for the carboxyl-containing moiety and for thering hydroxyl).

Refer to Chart A. Following the procedure of Example 4, the formula-XVIPGE₁ -type compound of Example 31 is transformed to the title compound;principle NMR spectral peaks at 6.57-7.3 (multiplet); 5.33-5.56(multiplet); 4.62 (singlet) and 3.75 (singlet) δ.

EXAMPLE 33 dl-3-Oxa-3,5-inter-m-phenylene-4-nor-PGE₃ Methyl Ester(Formula-XXXII; C_(j) H_(2j) and C_(p) H_(2p) are valence bonds in metarelationship, C_(n) H_(2n) is methylene, Q is ##EQU85## R₁ is methyl, R₅is ethyl, and ˜ is alpha) anddl-15-Beta-3-oxa-3,5-inter-m-phenylene-4-nor-PGE₃ Methyl Ester ##EQU86##

a. Refer to Chart F. Following the procedure of Preparation 4b, asolution of 100 g. of endo-bicyclo-[3.1.0 ]hexan-3-ol-6-carboxaldehyde3-tetrahydropyranyl ether in 200 ml. of benzene is reacted with 250 g.of (hex-3-ynyl)triphenylphosphonium bromide (Axen et al., Chem. Comm.1970, 602) in 3 l. of benzene at about -15° C. The mixture is warmed to70° C. for 2.5 hours., cooled and filtered. The crude product ishydrolyzed to the 3-hydroxy compound and then oxidized to the 3-oxoketone with Jones reagent. The desired fromula-LXIX intermediate isisolated after silica gel chromatography.

b. There is next prepared the formula-LXX compound by alkylation.Following the procedures of Example 1-B, the product of step a above isreacted with methyl9-chloro-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate(Preparation 7) to yield7-[endo-6-(cis-1-hepten-4-ynyl)-3-oxobicyclo[3.1.0]-hex-2α-yl]-3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-7-nonynoate.

c. Glycol LXXI is next prepared, employing the product of step b andfollowing the procedures of Example 2. Without separating the isomericglycols, the bismesylate corresponding to formula-LXXII is then preparedfollowing the procedures of Example 3. Thereafter, following hydrolysisof the bismesylate by the procedures of Example 3, the bisdehydro E₃type compound corresponding to formula-LXXIII is recovered. Silica gelchromatography yields the respective C-15 epimers.

d. Following the procedures of Preparation 8, each of the C-15 epimersof step C above is hydrogenated to yield the corresponding titlecompounds.

EXAMPLE 34 1-Bicyclo[3.1.0]hex-2-ene-6-endocarboxaldehyde NeopentylGlycol Acetal (Formula _(CIX) : R₃₁ and R₃₂ taken together are --CH₂--C(CH₃)₂ --CH₂ -- and ˜ is endo).

A mixture of 2,2-dimethyl-1,3-propanediol (900 g.), 5 l. of benzene and3 ml. of 85% phosphoric acid is heated at reflux. To it is added, in 1.5hr., a solution of optically activebicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde (Prep.10, 500 g.) in oneliter of benzene. Provision is made to take off azeotropically distilledwater with a Dean-Stark trap. After 3 hr. the mixture is cooled andextracted with 2 liters off 5% sodium bicarbonate. The organic phase isdried over sodium sulfate and concentrated under reduced pressure. Theresulting semisolid residue is taken up in methanol and recrystallized,using a total of 1200 ml. of methanol to which 600 ml. of water isadded, then chilled to -13° C. to yield 300 g. of the title compound,m.p. 52°-55° C., and having NMR peaks at 0.66, 1.20, 0.83-2.65,3.17-3.8, 3.96, and 5.47-5.88 δ, [α]_(D) - 227° (C=0.8976 in methanol),and R_(f) 0.60 (TLC on silica gel in 25% ethyl acetate in mixed isomerichexanes). Further work-up of the mother liquors yields 50-100 g. ofadditional product.

Following the procedures of Example 34 but replacing the aldehyde withoptically active bicyclo[3.1.0]hex-2-ene-6-exo-carboxaldehyde (see U.S.Pat. No. 3,711,515), there is obtained the corresponding formula-CIXacetal.

Following the procedures of Example 34 but using either the endo or exoform of the aldehyde and substituting for 2,2-dimethyl-1,3-propanediolone of the following glycols: ethylene glycol, 1,2-propanediol,1,2-hexanediol, 1,3-butanediol, 2,3-pentanediol, 2,4-hexanediol,2,4-octanediol, 3,5-nonanediol, 3,3-dimethyl-2,4-heptanediol,4-ethyl-4-methyl-3,5-heptanediol, phenyl-1,2-ethanediol and1-pentyl-1,2-propanediol, there are obtained the correspondingformula-CIX acetals.

EXAMPLE 35 d-8-(m-Acetoxyphenyl)-7-oxa-tricyclo-[4.2.0.0²,4]octane-6-endo-carboxaldehyde Neopentyl Glycol Acetal (Formula CX: C_(p)H_(2p) is a valence bond with attachment in the meta position, R₃₁ andR₃₂ taken together are --CH₂ --C(CH₃)₂ -CH₂, R₃₉ is ##EQU87## and ˜ isendo).

Refer to Chart L, step (a). A solution of the formula-CIXl-bicyclo[3.1.0]hex-2-ene-6-endo-carboxaldehyde neopentyl glycol acetal(Example 34, 5.82 g.) and m-acetoxybenzaldehyde (1.64 g.) in 25 ml. ofbenzene is charged to a Pyrex Photolysis vessel equipped with animmersible water-cooled cold-finger and a fritted gas inlet tube.Dissolved oxygen is removed by bubbling nitrogen through the solution.The mixture is then irradiated at 350 nm. with a Rayonet Type RSPreparative Photochemical Reacter (The Southern New England UltravioletCo., Middletown, Conn.) equipped with six RUL 3500 A lamps. After 24 hr.the photolysate is concentrated under reduced pressure to a pale yellowoil, 10 g., which is subjected to silica gel chromatography. Elutionwith 10-70% ethyl acetate in Skellysolve B (mixture of isomeric hexanes)yields separate fractions of the recovered starting material and theformula-CX title compound, a pale yellow oil, 0.86 g., having NMR peaksat 0.68. 1.20, 0.8-2.5, 2.28, 2.99, 3.12-3.88, 3.48, 4.97-5.52, and6.78-7.60 δ; infrared absorption bands at 3040, 2950, 2860, 2840, 1765,1610, 1590, 1485, 1470, 1370, 1205, 1115, 1020, 1005, 990, 790, and 700cm⁻ ¹ ; mass spectral peaks at 358, 357, 116, 115, 108, 107, 79, 70, 69,45, 43, and 41; [α]_(D) + 55° (C=0.7505 in 95% ethanol); and R_(f) 0.18(TLC on silica gel in 25% ethyl acetate in mixed isomeric hexanes).

Following the procedures of Example 35 but replacing the formula-CIXacetal with the formula-CIX compounds disclosed following Example 34,there are obtained the corresponding formula-CX compounds in their endoor exo forms and with corresponding exemplification of R₃₁ and R₃₂.

Likewise following the procedures of Example 35 but replacingm-acetoxybenzaldehyde with aldehydes within the scope of formula CXIXabove, as to C_(p) H_(2p), the attachment position of the phenyl ring,and the carboxyacyl group R₃₉, or defined above, the correspondingformula-CX oxetanes are obtained wherein ˜ is endo or exo, and R₃₁ andR₃₂ correspond to the glycols employed after Example 34 above.Specifically, the following formula-CXIX aldehydes are employed:##SPC139##

EXAMPLE 36d-2-Exo-[m-(pivaloyloxy)benzyl]-3-exobicyclo[3.1.0]hexane-6-endo-carboxaldehydeNeopentyl Glycol Acetal (Formula CXII: C_(p) H_(2p) is a valence bondwith attachment in the meta position, R₃₁ and R₃₂ taken together are--CH₂ --C(CH₃)₂ --CH₂ --, R₄₃ is ##EQU88## and ˜ is endo).

(I). Refer to Chart L, steps (b) and (c). A mixture of lithium (0.25 g.)in 70 ml. of ethylamine is prepared at 0° C. and cooled to -78° C. Asolution of the formula-CXd-8-(m-acetoxyphenyl)-7-oxa-tricyclo[4.2.0.0²,4]-octane-6-endo-carboxaldehyde neopentyl glycol acetal (Example 35, 1.83g.) in 10 ml. of tetrahydrofuran is added dropwise in about 5 min. Afterstirring at -78° C. for about 3.5 hr. the reaction is quenched withsolid ammonium chloride and water-tetrahydrofuran. Unreacted lithium isremoved, the mixture is warmed slowly to about 25° C., and ethylamine isremoved. The residue is neutralized with dilute acetic acid, mixed with200 ml. of brine, and extracted with ethyl acetate. The organic phase iswashed with brine and a mixture of brine and saturated aqueous sodiumbicarbonate (1:1), and dried over sodium sulfate. Concentration underreduced pressure yields the formula-CXI diol as a pale tan foamed oil,1.64 g., having R_(f) 0.03 (TLC on silica gel in 25% ethyl acetate inmixed isomeric hexanes).

(II). The product of part (I) is dissolved in 30 ml. of pyridine andtreated with 1.5 ml. of pivaloyl chloride over a period of 22 hr. atabout 25° C. The reaction mixture is mixed with water, then brine andextracted with ethyl acetate. The organic phase is washed successivelywith brine, water, saturated aqueous copper (II) sulfate, saturatedaqueous sodium bicarbonate, and brine, and dried over sodium sulfate.Concentration under reduced pressure yields a residue, 2.53 g., which issubjected to silica gel chromatography to yield the formula-CXII titlecompound, 1.87 g., having NMR peaks at 0.71, 1.20, 1.33, 0.9-3.1,3.28-4.00, 4.17, 4.7-5.2, and 6.77-7.53 δ; mass spectral peaks at 486,485, 115, 73, 72, 57, 44, 43, 42, 41, 30, 29, 15; [α]_(D) +10° (C=0.8385in ethanol); and R_(f) 0.50 (TLC on silica gel in 25% ethyl acetate inmixed isomeric hexanes).

EXAMPLE 37

d-2-Exo-(m-acetoxybenzyl)-3-exo-acetoxybixyclo]3.1.0]hexane-6-endo-carboxaldehydeNeopentyl Glycol Acetal (Formula CXII: C_(p) H_(2p) is a valence bondwith attachment in the meta position, R₃₁ and R₃₂ taken together are--CH₂ C(CH₃)₂ --CH₂ --, R₄₃ is ##EQU89## and ˜ is endo).

Following the procedure of Example 36-(II) but replacing pivaloylchloride with acetic anhydride, and using 1.01 g. of the formula-CXIdiol, there is obtained the title compound, 0.75 g., having NMR peaks at0.72, 1.22, 1.98, 2.27, 0.8-3.0, 3.28-3.85, 4.17, 4.75-5.22, and6.8-7.47 δ; mass spectral peaks at 402, 401, 115, 107, 73, 69, 45, 44,43, 42, 41, 30;[α]_(D) +7° (C=0.7060 in ethanol); and R_(f) 0.66 (TLC onsilica gel in 50% ethyl acetate in mixed isomeric hexanes).

EXAMPLE 382-Exo-[m-(pivaloyloxybenzyl]-3-exo-(pivaloyloxy)bicyclo[3.1.0]hexane-6-endo-carboxaldehyde(Formula CXIII: C_(p) H_(2p) is a valence bond with attachment in themeta position, R₄₂ is ##EQU90## and ˜ is endo).

Refer to Chart L step (d). The formula-CXII acetal, i.e.d-2-exo-[m-pivaloyloxy)benzyl]-3-exo-(pivaloyloxy)-bicycly[3.1.0]hexane-6-endo-carboxaldehydeneopentyl glycol acetal (Example 36, 0.48 g.) is treated at 0° C. with25 ml. of 88% formic acid for 4 hr. The mixture is diluted with 200 ml.of brine and extracted with ethyl acetate. The organic phase is washedwith brine and saturated aqueous sodium bicarbonate, and dried overmagnesium sulfate. Concentration under reduced pressure yields an oil,0.55 g., which is subjected to silica gel chromatography. Elution with5-15% ethyl acetate in Skellysolve B yields the formula-CXIII titlecompound as an oil, 0.37 g., having NMR peaks at 1.20, 1.33, 0.6-3.2,5.1-5.5, 6.6-7.5, and 9.73 δ; and R_(f) 0.50 (TLC on silica gel in 25%ethyl acetate in mixed isomeric hexanes).

EXAMPLE 39

2-exo-[m-(pivaloyloxy)benzyl]-3-exo-(pivaloyloxy)-6-endo-(cis-1-heptenyl)-bicyclo[3.1.0]hexane(Formula CXIV: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₄₂ is ##EQU91##

R₂ is hydrogen, and ˜ is endo); and2-Exo-(m-hydroxybenzyl)-3-exo-hydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula CXV : C_(p) H_(2p) is a valence bond in the meta position, G isn-pentyl, R₂ and R₄₂ are hydrogen, and ˜ is endo).

(I). Refer to Chart L, steps (e) and (f). The Wittig ylid reagent isprepared in 10 ml. of benzene from n-hexyltriphenylphosphonium bromide(0.79 g.) and n-butyllithium (0.6 ml. of 2.32 M. solution in hexane) atabout 25° C. for 0.5 hr. After the precipitated lithium bromdie hassettled, the solution is removed and added to a cold (0° C.) slurry ofthe formula-CXIII aldehyde (Examples 38, 0.37 g.). After 15 min. thereis added 1.0 ml. of acetone and the mixture is heated to 60° C. for 10min. The mixture is concentrated under reduced pressure. The residue iswashed with 10% ethyl acetate in Skellysolve B and these washings areconcentrated to the formula-CXIV title compound, an oil, 0.33 g. havingNMR peaks at 1.18, 1.33, 0.6-3.2, 4.5-6.0 and 6.67-7.62 δ; and R_(f)0.78 (TLC on silica gel in 25% ethyl acetate in Skellysolve B).

(II.) The above product of part (I) is transformed to the formula-CXVdiol by treatment with sodium methoxide (2.5 ml. of a 25% solution inmethanol) for 4 hr., followed by addition of 0.5 g. of solid sodiummethoxide and further stirring for 15 hr. at 25° C., then at reflux for6 hr. The mixture is cooled, mixed with 300 ml. of brine, and extractedwith ethyl acetate. The organic phase is washed with brine, dried overmagnesium sulfate, and concentrated under reduced pressure to a residue,0.27 g. The residue is subjected to silica gel chromatography, elutingwith 25-35% ethyl acetate in Skellysolve B, to yield the formula-CXVtitle compound an an oil, 0.21 g., having NMR peaks at 0.87, 0.6-3.25,3.88-4.35, 4.82-5.92, and 6.47-7.33 δ; and R_(f) 0.13 (TLC on silica gelin 25% ethyl acetate in Skellysolve B).

Following the procedures of Examples 36, 38, and 39 but replacing theformula CX oxetane with each of those obtained following Example 35,there are obtained successively the corresponding formula-CXI, -CXII,-CXIII, and -CXIV compounds wherein C_(p) H_(2p) and its attachmentposition on the phenyl ring correspond to the specific aldehydesemployed following Example 35. These are obtained in both their endo andexo forms.

Further following the procedures of Example 39, but replacing the Wittigylid reagent with one prepared from a compound of the formula

    Br--P(C.sub.6 H.sub.5).sub.3 --CHR.sub.2 --G

wherein --CHR₂ --G is each of the following:

--(CH₂)₃ --CH₃

--(ch₂)₄ --ch₃

--(ch₂)₆ --ch₃

--(ch₂)₇ --ch₃

--ch(ch₃)--(ch₂)₅ --ch₃

--ch₂ --ch(ch₃)--(ch₂)₃ --ch₃

--ch₂ --c(ch₃)₂ --(ch₂)₃ --ch₃

--ch(ch₃)--c(c₂ h₅)₂ --(ch₂)₃ --ch₃

--ch₂ --chf--(ch₂)₃ --ch₃

--ch₂ --cf₂ --(ch₂)₃ --ch₃

--ch(ch₃)--cf₂ --(ch₂)₃ --ch₃ ##SPC140##

--(ch₂)₂ --c.tbd.c--c₂ h₅

--ch₂ --ch(ch₃)--c.tbd.c--c₂ h₅

--ch₂ --c(ch₃)₂ --c.tbd.c--c₂ h₅

or

--CH(CH₃)--CH₂ --C.tbd.C--C₂ H₅

there are obtained the corresponding compounds within the scope offormula CXIV wherein C_(p) H_(2p) and its attachment to the phenyl ringcorrespond to the specific compounds of Example 39 and those illustratedin the paragraph immediately thereafter, in both their endo and exoforms.

EXAMPLE 402-Exo-{m-[(carboxy)methoxy]}-3-exo-hydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane(Formula CXVI : C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₁, R₂, and R₄₂ are hydrogen, and ˜ isendo).

Refer to Chart L, step (g). The formula-CXV diol, i.e.2-exo-(m-hydroxybenzyl)-3-exo-hydroxy-6-endo-(cis-1-hepentyl)bicyclo[3.1.0]hexane(Example 39, 0.19 g.) is treated in 8 ml. of dioxane with bromoaceticacid (0.61 g.) and 6 ml. of 1N. aqueous sodium hydroxide. After themixture has been heated at reflux for 3 hr., with sodium hydroxidesolution added when necessary to maintain a pH of about 10, the mixtureis cooled, diluted with 100 ml. of water, and extracted with diethylether. The aqueous phase is acidified to pH 1-2 and extracted with ethylacetate to yield the formula-CXVI title compound, a pale yellow oil,0.20 g. Recovered formula- CXV diol is obtained from the diethyl etherorganic phase on drying and concentrating, 0.025 g.

Following the procedures of Example 40 but replacing bromoacetic acidwith a haloacetate within the scope of Hal--CH₂ --COOR₁ as definedherein and specifically illustrated as follows

Cl--CH₂ --COOCH₃

Br--CH₂ --COOC₂ H₅

Cl--CH₂ --COOC₈ H₁₇ (n)

I--ch₂ --cooch₂ c₆ h₅

cl--CH₂ --COO(m-Cl--C₆ H₄)

there are obtained the corresponding formula-CXVI compounds wherein R₁is respectively methyl, ethyl, n-octyl, benzyl, and m-chlorophenyl.

Likewise following the procedures of Example 40 with each of theformula-CXIV compounds disclosed following Example 39 and using each ofthe haloacetates specifically identified above, there are obtained thecorresponding formula-CXVI compounds.

EXAMPLE 41 3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF₁.sub.α (FormulaCI : C_(p) H_(2p) is a valence bond with attachment in the metaposition, R₃₀ is n-pentyl, and R₁ and R₂ are hydrogen).

(I.) Refer to Chart L. The formula-CXVI alkene is transformed to thetitle compound applying the procedures disclosed in U.S. Pat. No.3,711,515. Thus, compound CXVI (Example 40) is hydroxylated by theprocedures of Example 39 of that patent to the formula-CXVII glycol ofChart L, using osmium tetroxide either alone or in combination withN-methylmorpholine oxide-hydrogen peroxide complex.

The glycol is then either (1) sulfonated, for example to yield thebismesylate, and then hydroyzed to a mixture of the title compound andits 15-epimer, applying the procedures of Example 7 of that patent, or(2) treated with substantially 100% formic acid to form the diformate ofCI and thereafter hydroyzed to a mixture of the title compound and its15 epimer, applying the procedures of Examples 20 and 21 of that patent.The epimers are separated by silica gel chromatography to yield thetitle compound and its 15-epimer.

(II). A third route from glycol CXVII to the title compound is by way ofa formula-CXX cyclic ortho ester ##SPC141##

wherein C_(p) H_(2p), R₄₆, R₄₇ and ˜ are as defined above. The glycolCXVII is treated as a 1-20% solution in benzene with trimethylorthoformate (1.5-10 molar equivalents) and a catalytic amount (1% ofthe weight of the glycol) of pyridine hydrochloride at about 25° C. Thereaction is followed by TLC (thin layer chromatography) and is completein a few minutes. There is thus obtained the formula-CXX cyclic orthoester in 100% yield.

The cyclic ortho ester is then treated with 20 volumes of 100% formicacid at about 25° C. In about 10 min. the reaction mixture is quenchedin water or aqueous alkaline bicarbonate solution and extracted withdichloromethane. The organic phase is shaken with 5% aqueous sodiumbicarbonate, dried over sodium sulfate, and concentrated to yield theformula CXXI diester, in this example identical with the diformate ofcompound CI. The diformate is contacted with 10-50 volumes of anhydrousmethanol and 10-20% of its weight of potassium carbonate at about 25° C.until the formyl groups are removed. The mixture of 15-epimers thusobtained is then separated to yield the formula-CI title compound andits 15-epimer.

Following the procedures of Example 41, each of the formula- CXVIalkenes disclosed following Example 40 is converted into thecorresponding oxa-phenylene PGF.sub.α analog and its 15-epimer. Thereare likewise formed the corresponding oxa-phenylene17,18-didehydro-PGF.sub.α analogs as shown in Chart N.

EXAMPLE 422-Exo-[m-(carboxymethoxy)benzyl]-3-exohydroxy-6-endo-(cis-1-heptenyl)bicyclo-[3.1.0]hexane(Formula CXXVII: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₁ and R₂ are hydrogen, and ˜ is endo).

Refer to Chart M, steps (a)-(f). There is first prepared theformula-CXXII oxetane. Following the procedures of Examples 34 and 35but replacing the m-acetoxybenzaldehyde of Example 35 with an aldehydewithin the scope of ##SPC142##

as to C_(p) H_(2p), the attachment position on the phenyl ring, and thecarboxyl group R₄₄, as defined above, the corresponding formula-CXXIIoxetanes are obtained with a fully developed side chain. Specifically,the following formula-CXXXI aldehydes are employed: ##SPC143##

Thereafter, following the procedures of Examples 36, 38, and 39, butreplacing the formula-XX ocetane of Example 36 with those obtained bythe procedure disclosed in the above paragraph of this example, thereare obtained the corresponding formula-CXXVI products. Likewisefollowing those procedures of Examples 36, 38, and 39, but replacing theWittig ylid reagent of Example 39 with each one disclosed after Example39, and applying it to each of the above formula-CX compounds of thisexample, there are obtained the corresponding formula-CXXVI compoundswith those specific sidechains.

Finally, the blocking groups on each CXXVI compound are removed bymethods disclosed herein or known in the art to yield the formula-CXXVIItitle compound and the corresponding formula-CXXVII compounds from thoseformula-CXXVI compounds above.

EXAMPLE 43 2-Exo-{m-[(methoxycarbonyl)methoxy]benzyl{-3-exohydroxy-6-endo-(cis-1-heptenyl)bicyclo[3.1.0]hexane (Formula-CXXVII:C_(p) H_(2p) is a valence bond with attachment in the meta position, Gis n-pentyl, R₁ is methyl, R₂ is hydrogen, and ˜ is endo).

Refer to Chart M. The formula-CXXVII acid (Example 40, 0.20 g.) istreated in methanol solution at 0° C. with a solution of diazomethane indiethyl ether (prepared from N-methyl-N-nitroso-N'-nitroguanidine (2.0g.) and potassium hydroxide (6 ml. of 40% aqueous solution)) until apermanent yellow color is produced, and the mixture is concentrated toyield the title compound, a pale tan oil.

EXAMPLE 44l-6-Endo-(cis-1-heptenyl)-2-exo-{m-[(methoxycarbonyl)methoxy]benzyl}bicyclo[3.1.0]hexan-3-one(Formula CXXVIII: C_(p) H_(2p) is a valence bond with attachment in themeta position, G is n-pentyl, R₁ is methyl, R₂ is hydrogen, and ˜ isendo).

Refer to Chart M, step (g). The formula-CXXVII methyl ester is oxidizedto the bicyclic hexanone as follows. The formula-CXXVII methyl ester(Example 41, 0.21 g.) is added in 2 ml. of dichloromethane to a solutionof Collins reagent (prepared from pyridine (0.53 g.) and chromiumtrioxide (0.34 g.) in 10 ml. of dichloromethane) at about 25° C. for 15min. The mixture is then shaken with a mixture of 60 ml. of diethylether, ice, and 25 ml. of 1 N. aqueous sodium hydroxide, and the organicphase is separated. The organic phase is washed with 1 N. aqueous sodiumhydroxide, 1.2 N. aqueous hydrochloric acid, and brine, dried, andconcentrated under reduced pressure. The residue, a colorless oil, 0.19g., is subjected to silica gel chromatography, eluting with 5- 20% ethylacetate in Skellysolve B. There is thus obtained the formula-CXXVIIItitle compound, a colorless oil, 0.13 g., having NMR peaks at 0.87,0.6-3.3, 3.77, 4.60, 4.5-5.1, 5.37-5.95, and 6.58-7.40 δ; [α]_(D) -39°(C=0.8380 in 95% ethanol); and R_(f) 0.42 (TLC on silica gel in 25%ethyl acetate in Skellysolve B).

Following the procedures of Examples 43 and 44, each of theabove-identified formula-CXXVII compounds following Example 42 isoxidized to the corresponding formula-CXXVIII compound.

EXAMPLE 45 3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGE₁, Methyl Ester(Formula XCVII: C_(p) H_(2p) is a valence bond with attachment in themeta position, R₁ is methyl, R₃₀ is n-pentyl, and R₂ is hydrogen).

Following the procedures of Example 41, the formula-CXXVIII alkene istransformed in several steps to the title compound.

Likewise, following the same procedures, each of the formula-CXXVIIIalkenes disclosed following Example 44 is converted into thecorresponding oxa-phenylene PGE analog and its 15 -epimer.

Following the procedures of Examples 34-45, each of the endointermediates is replaced by the corresponding exo intermediate to yieldthe corresponding exo intermediate or the ultimate oxa-phenylene PGanalog.

Likewise following the procedures of Examples 34-45, each of theoptically active isomers is replaced by the corresponding racemicmixture to yield the corresponding racemic intermediate or ultimateoxa-phenylene PG analog.

I claim:
 1. An optically active compound of the formula: ##SPC144##or aracemic mixture of that compound and the enantiomer thereof, whereinC_(j) H_(2j) represents a valence bond or alkylene of one or 2 carbonatoms, with one chain carbon atom between --CH=CH-- and the phenylenering; wherein C_(p) H_(2p) represents a valence bond or alkylene of oneto 4 carbon atoms, inclusive, with one or 2 chain carbon atoms betweenthe ring and --O--; wherein C_(j) H_(2j) and C_(p) H_(2p) togetherrepresent zero to 6 carbon atoms, inclusive, with total chain lengthszero to 3 carbon atoms, inclusive; wherein G is (1) alkyl of 2 to 10carbon atoms, inclusive, substituted with zero, one, 2, or 3 fluoro or(2) a monovalent moiety of the formula ##SPC145## wherein C_(t) H_(2t)represents a valence bond or alkylene of one to 10 carbon atoms,inclusive, substituted with zero, one, or 2 fluoro, with one to 7 carbonatoms, inclusive, between ##EQU92## and the ring, wherein T is alkyl ofone to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or--OR₆, wherein R₆ is hydrogen or alkyl of one to 4 carbon atoms,inclusive, and wherein s is zero, one, 2, or 3, with the proviso thatnot more than two T's are other than alkyl; wherein Q is ##EQU93##wherein R₂ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro oralkyl of one to 4 carbon atoms, inclusive, wherein ˜ indicatesattachment of the side chain to the cyclopentane ring in alpha or betaconfiguration; including the lower alkanoates thereof and thepharmacologically acceptable salts thereof when R₁ is hydrogen.
 2. Acompound according to claim 1 wherein G is alkyl of 2 to 10 carbonatoms, inclusive, substituted with zero, one, 2, or 3 fluoro.
 3. Acompound according to claim 2 wherein ˜ indicates attachment of the sidechain to the cyclopentane ring in alpha configuration.
 4. A compoundaccording to claim 3 wherein Q is ##EQU94##
 5. A compound according toclaim 4 wherein R₁ is hydrogen or alkyl of one to 12 carbon atoms.
 6. Acompound according to claim 4 wherein R₁ is hydrogen, methyl, or ethyl.7. A compound according to claim 5 wherein R₂ is hydrogen.
 8. A compoundaccording to claim 5 wherein R₂ is methyl or ethyl.
 9. A compoundaccording to claim 5 wherein C_(j) H_(2j) is a valence bond.
 10. Acompound according to claim 9 wherein C_(p) H_(2p) is methylene.
 11. Acompound according to claim 9 wherein C_(p) H_(2p) is a valence bond.12. A compound according to claim 11 wherein G is ##EQU95## wherein a isone, 2, 3, 4, or 5, and wherein R₂₁ and R₂₂ are hydrogen, alkyl of oneto 4 carbon atoms, inclusive, or fluoro, being the same or different,with the proviso that R₂₂ is fluoro only when R₂₁ is hydrogen or fluoro.13. A compound according to claim 12 wherein a is 2, 3, or 4, andwherein R₂₁ and R₂₂ are hydrogen, methyl, ethyl, or fluoro, being thesame or different.
 14. 3-Oxa-3,5-inter-m-phenylene-4-nor-PGE₂, acompound according to claim
 11. 15.3-Oxa-3,5-inter-m-phenylene-4-nor-PGE₂, methyl ester, a compoundaccording to claim
 11. 16.15(S)-15-Methyl-3-oxa-3,5-inter-m-phenylene-4-nor-PGE₂, a compoundaccording to claim
 11. 17.16,16-Dimethyl-3-oxa-3,5-inter-m-phenylene-4-nor-PGE₂, a compoundaccording to claim
 11. 18. A compound according to claim 1 wherein G isa monovalent moiety of the formula ##SPC146##wherein C_(t) H_(2t)represents a valence bond or alkylene of one to 10 carbon atoms,inclusive, substituted with zero, one, or 2 fluoro, with one to 7 carbonatoms, inclusive, between ##EQU96## and the ring, wherein T is alkyl ofone to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or--OR₆, wherein R₆ is hydrogen or alkyl of one to 4 carbon atoms,inclusive, and wherein s is zero, one, 2, or 3, with the proviso thatnot more than two T's are other than alkyl.
 19. A compound according toclaim 18 wherein ˜ indicates attachment of the side chain to thecyclopentane ring in alpha configuration.
 20. A compound according toclaim 19 wherein Q is ##EQU97##
 21. A compound according to claim 20wherein R₁ is hydrogen or alkyl of one to 12 carbon atoms.
 22. Acompound according to claim 20 wherein R₁ is hydrogen, methyl, or ethyl.23. A compound according to claim 21 wherein R₂ is hydrogen.
 24. Acompound according to claim 21 wherein R₂ is methyl or ethyl.
 25. Acompound according to claim 21 wherein C_(j) H_(2j) is a valence bond.26. A compound according to claim 25 wherein C_(p) H_(2p) is methylene.27. A compound according to claim 25 wherein C_(p) H_(2p) is a valencebond.
 28. A compound according to claim 27 wherein G is##SPC147##wherein e is zero, one, 2, or 3; wherein R₂₁ and R₂₂ arehydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, beingthe same or different, with the proviso that R₂₂ is fluoro only when R₂₁is hydrogen or fluoro; wherein T is alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₆, wherein R₆ ishydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein s iszero, one, 2, or 3, with the proviso that not more than two T's areother than alkyl.
 29. A compound according to claim 28 wherein R₂₁ andR₂₂ are hydrogen, methyl, ethyl, or fluoro, being the same or different.30. 3-Oxa-3,7-inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor-PGE₂, acompound according to claim
 27. 31.15(S)-15-Methyl-3-oxa-3,7-inter-m-phenylene-17-phenyl-4,5,6,18,19,20-hexanor-PGE₂,a compound according to claim 27.